Introduction
The advancement of technology and medicine increased the individual’s average age. With a decreasing fertility and mortality rate, a significant proportion of the population is becoming older (Kowal et al., 2016). Older individuals are more susceptible to age-associated diseases including stroke, dementia, diabetes, cardiovascular disease, and cancer (Jaul and Barron, 2017). The anatomy and homeostasis of the brain change with aging (Juraska and Lowry, 2012) and the aged brain respond differently to injury and stress than the brain of a young adult. Interestingly, the neuronal density remains stable throughout the lifespan however, 30% of individuals suffer from severe cognitive impairment without meeting the criteria of Alzheimer’s disease (AD) or dementia (Harada et al., 2013). Results from MRI and histological analysis studies demonstrate a decline in white matter volume which corroborated with cognitive impairment in healthy aged individuals (Fjell and Walhovd, 2010; Coelho et al., 2021). The myelin sheath damage leads to white matter vulnerability resulting in axonal damage producing disconnect that could attribute to cognitive impairment (Kohama et al., 2012; Peters and Kemper, 2012; Faizy et al., 2020). A complex interplay between myelin plasticity, oligodendrocyte maturation, removal and clearance of myelin debris, and remyelination supports myelin maintenance and homeostasis and these processes decline with age (Soreq et al., 2017; Spitzer et al., 2019; Sams, 2021). Experimental studies have shown that oligodendrocyte precursor cells fail to mature into myelinating oligodendrocytes and aged animals demonstrate limited ability to replenish oligodendrocyte precursor cells pool thus is partially responsible for age-related reduced remyelination and myelin repair (Shields et al., 2000; Neumann et al., 2019; Ito et al., 2021). Microglia plays an important role in oligodendrocyte precursor cell differentiation into mature oligodendrocytes, removes myelin debris, and promotes remyelination, however, this function declines with age (Kalafatakis and Karagogeos, 2021; Luan et al., 2021), thus prompting cognitive dysfunction. Several genes are expressed by microglia that promote lymphocyte infiltration in the aged brain exacerbating the white matter injury and contributing to cognitive impairments in aged individuals. Thus an interplay between microglia and lymphocytes not only contributes to age-associated brain injury but their precise role in stroke pathophysiology in older subjects has not been fully explored.
The objective of this review is to summarize the evidence that both microglia and lymphocytes are involved in the process of aging. The interplay of microglia and lymphocytes negatively modulates cognition in older subjects after stroke. Finally, we present the studies targeting therapeutic strategies toward microglia or lymphocytes in older animals after stroke. The review will aid in better understanding the contribution of microglia and lymphocytes in post-stroke functional outcomes that happen to be a major concern in older individuals.
Retrieval Strategy
The studies cited in this review were retrieved from Google scholar and PubMed databases. The relevant literature published from January 1994 to September 2022 was screened. A combination of the following words (MeSH terms) was used to maximize search specificity and sensitivity: age, cognition, microglia, T lymphocytes, B lymphocytes, stroke, white matter, neuroinflammation, and brain. The results were further screened by title and abstract and studies exploring the relationship between microglia, and lymphocytes in aging were included. Furthermore, the role of microglia and lymphocytes and their contribution to stroke neuroinflammation was included. No language or study type restrictions were applied. Articles involving studies investigating the contribution of young microglia and lymphocytes in stroke were excluded. No limit was used on the year of publication or authorship.
Aged Microglia Contributes to Cognitive Impairment
One of the cell types that is profoundly affected by age is brain resident macrophages- microglia. Microglia are primary immune cells that constitute 10% of all cells in the adult brain (Pessac et al., 2001). Microglia acquire a dystrophic and dysfunctional phenotype with age (Safaiyan et al., 2016; Cantuti-Castelvetri et al., 2018; Deczkowska et al., 2018). A multitude of factors including cellular aging, transcriptomic changes, senescence-associated secretory phenotype, dysregulated microglia metabolism, and the milieu that these cells reside could influence the microglia behavior (Minhas et al., 2021). Activated microglia secrete multiple pro-inflammatory cytokines including interleukin (IL)-1β (Figure 1). Cathepsin B is associated with the production and secretion of IL-1β and leakage of cathepsin B, a lysosomal enzyme from the endosomal/lysosomal system is observed with aging thus, cathepsin B plays a major role in brain aging (Nakanishi, 2020). Genetic depletion of cathepsin B in middle-aged mice resulted in decreased microglia-dependent reactive oxygen species (ROS) generation, inflammation, and improvement in age-dependent cognitive impairments (Ni et al., 2019). Overexpression of cathepsin B in hippocampus microglia of middle-aged mice leads to cognitive impairments validating the contribution of microglia lysosomal function in cognitive impairment in old animals (Ni et al., 2019).
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Figure 1: Microglia become dysregulated with aging.Aged microglia are robust producers of pro-inflammatory cytokines, and generate reactive oxygen species (ROS), and inflammatory signaling pathways are activated. Accumulation of myelin debris, lipofuscin, and lipid droplets is observed in aged microglia. PGE2: Prostaglandin E2.
With age, microglia and macrophages have increased lipid messenger prostaglandin E2 (PGE2) signaling (Breyer et al., 2001; Minhas et al., 2021). PGE2 promotes the conversion of glucose to glycogen resulting in reduced glucose influx and mitochondrial respiration thus enhancing inflammatory responses (Casolini et al., 2002; Wu and Meydani, 2004). Enhanced PGE2 signaling has been shown to promote cognitive impairment in rodents (Xiao et al., 2018; Zhao et al., 2019; Minhas et al., 2021). Increased macrophages and microglia PGE2 signaling have been shown to induce age-associated cognitive impairment (Minhas et al., 2021; Figure 1). Inhibition of peripheral PGE2 signaling in aged mice restored hippocampal CA1 long-term potentiation and improved mitochondrial coupling of electron transport and ATP synthesis (Minhas et al., 2021) thus confirming the detrimental role of PGE2 signaling in age-associated cognitive functions.
A decline in microglia phagocytic function has been shown to increase in aged microglia (Pluvinage et al., 2019; Yanguas-Casas et al., 2020). CD36, a protein involved in phagocytosis is decreased in senescent microglia (Rawji et al., 2020). Upregulation of CD36 in cultured microglia improved myelin phagocytic activity and treatment with niacin in 9–12-month-old (middle-aged) demyelinated mice promoted myelin debris clearance, increased oligodendrocyte precursor cells, and improved remyelination (Rawji et al., 2020). Additionally, CD22, a sialic acid binding immunoglobin-like lectin expressed on B cells was found to be upregulated in aged microglia (Pluvinage et al., 2019). CD22 negatively regulates BCR signaling and has been shown to modulate leucocyte phagocytosis in fish (Nitschke et al., 1997; Li et al., 2019). A recent study by Pluvinage et al. (2019) showed inhibition of CD22 promoted myelin debris removal in vitro and central nervous system (CNS) delivery of antibodies against CD22 reprogrammed microglia towards homeostatic transcriptional state and improved cognitive functions in older mice, thus suggesting that restoration of microglia phagocytosis might improve memory in older individuals.
Macrophages depend on colony-stimulating factor-1 receptor (CSF-1R) signaling for survival, proliferation, and differentiation (Stanley and Chitu, 2014; Pluvinage et al., 2019). Inhibition of CSF-1R signaling has been shown to result in a reversible decline in the microglia population (Elmore et al., 2014; Spangenberg et al., 2016, 2019). Depletion of aged microglia by using CSF-1R inhibitor, PLX5622, and repopulation restored age-associated cognitive impairment and increased neurogenesis in older rodents (Elmore et al., 2018). However, a recent study showed that the depletion of microglia by PLX5622 and repopulation resulted in a partial reversal of primed microglia in aged mice (Elmore et al., 2018). As the repopulated microglia demonstrated exaggerated pro-inflammatory responses when challenged with lipopolysaccharide. Furthermore, inflammatory gene transcriptome persisted in the brain even after microglia was repopulated in aged animals thus suggesting the presence of an inflammatory environment in older brains (Elmore et al., 2018; O’Neil et al., 2018). Similar results were observed by microglia depletion and repopulation in aged BALB/c mice. Microglia repopulation reversed age-associated defects in microglia CD68+ lysosome enlargement and lipofuscin accumulation (O’Neil et al., 2018). Lipofuscin accumulation has been seen in aged microglia and leads to impaired microglia functions and cell death (Streit et al., 2014; Safaiyan et al., 2016; Burns et al., 2020). The lipopolysaccharide challenge following repopulation in both young and aged animals demonstrated heightened microglia responses compared to young mice (O’Neil et al., 2018) thus reflecting that microglia renewal does not influence the microenvironment in the aged brain. Additionally, microglia repopulation failed to restore synaptic transmission and cognition in aged animals suggesting that aged microglia support synaptic and cognitive functions in older subjects (Yegla et al., 2021).
Microglia and Lymphocytes Interact with Age
The detrimental contribution of microglia towards age-associated cognitive decline is well characterized, however, little is known about how innate immune cells including T and B lymphocytes might in involved in brain aging. As microglia and lymphocytes communicate in the aged brain it becomes imperative to understand the underlying mechanisms that lead to age-associated cognitive impairments.
Several genes associated with microglia activation interact with infiltrated T lymphocytes and could play a role in neurodegenerative diseases and aging (Schetters et al., 2017; Groh et al., 2021). With aging, microglia tend to shift towards pro-inflammatory status and secrete TNF-α, IL-6, and IL-1β (Hickman et al., 2013; Ritzel et al., 2015; Zhang et al., 2022b). The expression of adhesion molecules, chemokines, and their receptors control the immune cell migration across the blood-brain barrier (BBB) (Marchetti and Engelhardt, 2020). TNF-α has been shown to upregulate the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 (ICAM-1) on venous endothelial cells and promoted T cell transmigration (Zhang et al., 2022b). Aged microglia release CCL-3 resulting in the recruitment of CD8+ memory T cells into the SV zone thus resulting in age-related neuroinflammation (Zhang et al., 2022b). A study by Groh et al. (2021) reported an increase in CD8+ T cells in the WM regions in both aged mice and old humans. The microglia acting as antigen-presenting cells contributed to CD8+ T cell-mediated axonal degeneration, and cognitive and motor impairment in aged animals. Interestingly in their Sc-RNA sequencing data, the authors reported an age-related increase in CD8+ T cell subgroups some of which could be protective (Urban et al., 2020).
Tumor necrosis factor-α-induced protein 3 or A20 is expressed on microglia and has been shown to maintain brain homeostasis (Urban et al., 2020). A20 is a key regulator in NF-κB signaling which has been shown to promote inflammation and aging (Tilstra et al., 2011; Liu et al., 2017). Loss of A20 in microglia resulted in a microglial pro-inflammatory phenotype (Voet et al., 2018; Mohebiany et al., 2020). A20 deficient microglia upregulated IL-6, CCL-2, and CCL-3 and promoted brain infiltration of CD8+ T cells. CD8+ T cells have been shown to produce IFN-γ which leads to neuroinflammation and neurological damage (Akwa et al., 1998; Campbell et al., 1999). IFN-γ has been shown to have detrimental effects in the neurogenic niche during aging (Dulken et al., 2019; Kalamakis et al., 2019). Interestingly, the loss of microglia A20 with aging has not been investigated however it is plausible that aged microglia acquire an inflammatory phenotype due to deficiency of A20, and this needs further investigation.
Role of T Lymphocytes in Aging and Cognition
Recent studies have derailed the conventional wisdom that CNS is immune-privileged tissue and peripheral immune cells only invade the brain when there is damage to the BBB. With aging the BBB becomes leaky and T cells may be able to infiltrate the brain parenchyma (Yang et al., 2020; Figure 2) and contribute to age-associated cognitive impairment. Incidentally, the presence of T cells has been demonstrated in WM, subventricular zone (SV) zone, meninges, and choroid plexus (CP) and exerts pathological effects with aging in both humans and non-human primates and rodents (Baruch et al., 2013; Dulken et al., 2019; Moreno-Valladares et al., 2020a, b; Batterman et al., 2021; Berry et al., 2021; Brioschi et al., 2021; Schafflick et al., 2021; Korf et al., 2022; Zhou et al., 2022). Rustenhoven et al. elegantly demonstrated an increase in sinus and non-sinus T lymphocytes with age in mice (Rustenhoven et al., 2021). T lymphocytes upon brain-derived antigen presentation could be recruited to meninges and infiltrate brain parenchyma (Ellwardt et al., 2016; Rustenhoven et al., 2021) migrating to myelin-rich regions (Groh et al., 2021) and negatively regulating cognition. Da Mesquita et al. (2021) demonstrated an increase in meningeal CD4+ FOXP3+T regs in aged animals thus linking meningeal immunity to cognitive impairment. Removal of these cells by anti-CD25 antibodies resulted in a decrease in meningeal CD4+FOXP3+T regs and improvement in cognition in aged mice reflecting that modulation of meningeal immunity could improve age-associated cognitive dysfunction (Da Mesquita et al., 2021). CNS-specific effector memory CD4+ T cells have been shown to increase in aged CP and are robust producers of IL-4 (Baruch et al., 2013). Increased levels of IL-4 promoted CCL-11 by CP epithelium, a chemokine associated with cognitive impairment with aging (Villeda et al., 2011). However, there is less known about how CD4+ T cells infiltrate aged brain parenchyma and modulate normal aging processes. Batterman et al. (2021) found an age-associated increase in the infiltrated T cells in the cingulum bundle and WM of aged rhesus monkeys. Furthermore, the T cell density in the cingulum bundle correlated with microglia reactivity and cognitive impairment (Batterman et al., 2021). On the contrary, Berry et al. (2021) reported no difference in the human cortex T cells with age reflecting that regional differences could influence T cell infiltration in the aged brain.
Figure 2: The presence of T and B lymphocytes in the healthy brain and after stroke.T and B lymphocytes are present in white matter, subventricular zone, meninges, and CP in the human brain with aging (A). After the stroke, the lymphocytes transmigrate to the injured parenchyma from CP, meninges, sinus, and leaky blood brain barrier (BBB; B). BBB breakdown, and migration of immune cells after stroke (C). CP: Choroid plexus; CSF: cerebrospinal fluid; ICAM-1: intercellular adhesion molecule-1; VCAM-1: vascular cell adhesion molecule-1.
Tissue-resident memory T cells are seen in human and rodent brains (Ritzel et al., 2016; Smolders et al., 2018). A recent study demonstrated oligoclonal T cells with tissue-resident memory gene signatures in the neurogenic niches in the aged brain (Dulken et al., 2019). These antigen-specific CD8+ T resident memory T cells were found in the CNS after peripheral immunizations and showed protection against brain infections (Urban et al., 2020) suggesting some T lymphocytes can have protective roles. Studies showed elevated infiltrated CD8+T cells in the SV zone with age in both mice and humans (Dulken et al., 2019; Moreno-Valladares et al., 2020a). The exact mechanism that leads to the infiltration of CD8+ T cells in the aged brain is not fully delineated. However, studies report the critical role of microglia.
Role of B Lymphocytes in Aging
A small number of B and plasma cells have been reported in healthy human cerebrospinal fluid (CSF) (Prasad, 1983; Rojas et al., 2020) and brain parenchyma (Frischer et al., 2009; Machado-Santos et al., 2018; Jain and Yong, 2022). They are usually observed in perivascular spaces including meninges and dura mater (Frischer et al., 2009; Howell et al., 2011; Machado-Santos et al., 2018). Unfortunately, there is only one study that has reported B cell density in the human-aged brain (Berry et al., 2021). In this study, the authors reported a lower B cell density (7.8 ± 1.4 cells/cm2) in young versus aged human subjects (6.2 ± 1.0 cells/cm2) (Berry et al., 2021). In mice, B cells are rarely present in the healthy brain parenchyma but are found in small numbers in CSF, CP, and subdural meninges (Korin et al., 2017; Brioschi et al., 2021; Schafflick et al., 2021). B lymphocytes have been shown to occur in dural meninges and account for 15–30% of all CD45hi leukocytes (Korin et al., 2017; Brioschi et al., 2021; Schafflick et al., 2021). Most of these cells in the dural meninges are B2 B cells and the vast majority are immature B cells generated in the skull bone marrow (Brioschi et al., 2021; Schafflick et al., 2021). B cells in the brain are tissue-resident, generated locally (Brioschi et al., 2021; Schafflick et al., 2021). Mature CNS B cells are IgM+ cells with unmutated BCRs although few IgA+ B cells are also observed (Brioschi et al., 2021; Schafflick et al., 2021). In the young mice, the integration of peripheral B cells into the resident CNS pool is very limited however it increases with age and tends to demonstrate T bet+ B cells which is consistent with age-associated B cells (Rubtsova et al., 2015; Korf et al., 2022). In young mice, IgA+ plasma cells comprise most of the B cells in the meninges that are partially derived from the gut (Fitzpatrick et al., 2020). However, with an increase in age, IgG+ and IgM+ plasma cells become common in the meninges (Brioschi et al., 2021). Recently, we have shown the presence of CD11bhi B cells in the mouse brain that have a distinct phenotype and are robust producers of TNF-α (Korf et al., 2022). CD11b is expressed by myeloid cells as well as B cells and regulates cell motility and phagocytosis (Liu et al., 2015; Schittenhelm et al., 2017).
CD11bhi B cell counts increased in the spleen, skull bone marrow, and brain of the aged mice compared to young animals. These cells had higher expression of CD138 (expressed by plasma cells) (Sanderson et al., 1989), memory markers (CD80 and CD27) (Wu et al., 2011; Good-Jacobson et al., 2012), CD73 (class switched) (Schneider et al., 2019), and CD268 shown to be expressed by autoreactive B cells (Liu et al., 2015; Qian et al., 2019). Additionally, a decrease in IgD and no change in IgM were consistent with age-associated B cells (Hao et al., 2011; Rubtsov et al., 2011; Rubtsova et al., 2015). Upon lipopolysaccharide stimulation, sorted CD45+CD19+B cells increased CD11b expression and had higher T-bet expression and increased uptake of beads in phagocytic assay suggesting enhanced phagocytic activity. B cells have been shown to increase the production of TNF-α on activation (Ma et al., 2019) and we observed higher expression of TNF-α on CD45+CD19+CD11bhi B cells hence reflecting a mixed, activated, and heterogeneous B cell population.
To understand the contribution of CD45+CD19+CD11bhi B cells in modulating the functions of microglia we used PepBoy mice which has a distinguishable CD45 haplotype (CD45.1) than C57BL/6 express Ptprc (CD45.2) allele. The CD11bhi and CD11blow B cells were sorted from aged spleens and retro-orbitally transferred to young PepBoy mice. Twenty-four hours post-injection, the microglia expression of CD11b increased additionally an increase in bead uptake was observed consistent with phagocytic activity in mice treated with aged CD11bhi B cells than the aged CD11blow B cells. These results suggested that the presence of CD11bhi B cells could be partially responsible for microglia dysfunction (Korf et al., 2022). Microglia-mediated neuroinflammation contributes toward age-associated cognitive impairment. However, further research is warranted to delineate the functions of CD11bhi B cells in aging and age-associated cognitive impairment.
Aged Microglia in Stroke
Stroke is the second leading cause of death and disability worldwide (Collaborators, 2019), and approximately two-thirds of all strokes occur in older adults (Feigin et al., 2014). Increased risk of stroke and poor stroke-related outcomes in older individuals already represent major challenges to the current healthcare system (Go et al., 2014). Findings from our laboratory and others demonstrate differential infarct and functional outcomes after stroke in young and aged animals (Sutherland et al., 1996; Kharlamov et al., 2000; Chauhan et al., 2017; Ritzel et al., 2018). Some studies demonstrate larger infarcts in older animals whereas others have shown smaller infarct sizes than those observed in young subjects (Sutherland et al., 1996; Kharlamov et al., 2000; Chauhan et al., 2017; Ritzel et al., 2018). Irrespective of the discrepancy in infarct size, aged animals have worse functional outcomes and increased mortality post-stroke in comparison to young animals (DiNapoli et al., 2008; Tan et al., 2013; Wang et al., 2013; Suenaga et al., 2015). In response to cerebral injury, microglia are some of the first responders, who quickly develop an activated phenotype (M1), generate reactive oxygen species, phagocytize, and produce pro-inflammatory cytokines and proteases (Macrez et al., 2011; Taylor and Sansing, 2013). In addition, microglia also produce anti-inflammatory cytokines (M2), including IL-4 and IL-10, which play important role in the resolution and the restorative phase of stroke. Dystrophic changes and age-associated microglia activation have been reported in aged rodents, humans, and non-human primates (Perry et al., 1993; Streit and Sparks, 1997; Sheffield and Berman, 1998). Removal of microglia in young mice by PLX 3397 prior to stroke resulted in increased infarct size, due to dysregulated neuronal calcium responses and increased neuronal cell death (Szalay et al., 2016). Additionally, the young microglia do not have dysfunctional phenotype hence we tested our hypothesis that the removal of activated microglia in aged mice will improve acute functional recovery. The aged mice were fed with CSF-1R inhibitor (PLX 5622) 3 weeks before the stroke. Depletion of aged microglia resulted in increased infarct volume and acutely after the middle cerebral artery occlusion (MCAO) model. We further validated our findings by administering a monoclonal antibody against CSF-1R directly into the brain. An increase in infarct volume and increased infiltrated monocytes in the aged mice after stroke was seen in animals in which microglia were depleted (Marino Lee et al., 2021). The increase in post-stroke injury after microglia removal in aged could partially be explained by a higher number of infiltrating monocytes in the mice that were fed with PLX5622. Acute monocyte infiltration has been shown to worsen stroke outcomes in young mice (Fang et al., 2018). Additionally, the removal of microglia by PLX5622 promoted GFAP+ reactive astrocytes which could be responsible for enchased brain injury after stroke (Stadler et al., 2022).
RNA sequencing studies have shown upregulation or downregulation of different sets of genes after stroke in aged microglia (Jiang et al., 2020; Shi et al., 2020). After distal MCAO, upregulation of genes involved in cell motility, cell interactions, angiogenesis, and inflammatory responses was observed in young microglia whereas the aged microglia had reduced or no changes in the genes involved in these processes (Jiang et al., 2020; Shi et al., 2020). Reduced chemotaxis and failure of increased expression of genes involved in cell-to-cell interaction, tissue remodeling, and angiogenesis were apparent in the aged microglia during the recovery phases of the stroke (Jiang et al., 2020; Shi et al., 2020) thus highlighting the difference in the post-stroke transcriptome in aged microglia.
WM damage is present after stroke in both rodents and humans (Fu et al., 2005; Li et al., 2013; Suenaga et al., 2015; Marin and Carmichael, 2018; Etherton et al., 2019; Faheem et al., 2019; Hong et al., 2021). Incidentally, aged animals are more sensitive to WM damage, increased oligodendrocyte death, oxidative stress, and poor functional recovery after stroke (Rosenzweig and Carmichael, 2013; Suenaga et al., 2015). Increased myelin fragmentation with age resulted in the accumulation of undegradable lysosomal aggregates in aged microglia (Safaiyan et al., 2016). Lysosomes attached to lipid droplets have been reported in aged microglia suggesting lipid cycling through lipophagy (Vaughan and Peters, 1974). Lipid droplet accumulating microglia has been identified in the aged human and rodent brain and represents a dysfunctional phenotype (Foley, 2010; Marschallinger et al., 2020; Arbaizar-Rovirosa et al., 2022). Studies have shown that stroke induces lipid droplet biogenesis in both young and aged microglia and plays a role in lipid metabolism and phagocytosis (Beuker et al., 2022; Arbaizar-Rovirosa et al., 2022). Accumulation of lipid droplets in chronic stroke has been shown to impair post-stroke recovery (Becktel et al., 2022). Repopulation of microglia after cessation of the PLX5622 diet in aged stroke animals increased expression of genes involved in long-chain fatty acid metabolism and cholesterol biosynthesis and metabolism (Arbaizar-Rovirosa et al., 2022). Renewal of microglia in old stroke mice resulted in reduced microglia lipid droplet content and improvement in functional outcomes (Arbaizar-Rovirosa et al., 2022) reflecting rejuvenation of certain metabolic pathways after microglia repopulation. Suenaga et al. (2015) demonstrated greater WM damage, and reduced M2 polarized microglia in the aged mice correlated with worse functional outcomes. M2 microglia promotes recovery processes including neurogenesis, angiogenesis, WM repair, and release of neurotrophic factors thus resolving inflammation (Hu et al., 2015; Suenaga et al., 2015). However, all these processes have been shown to be impaired in aged mice after stroke and could be responsible for worse functional outcomes (Walter et al., 2010; Manwani et al., 2011; Tang et al., 2016; Ritzel et al., 2018).
T and B Lymphocytes in Aged Stroke
T and B lymphocytes in clinical stroke in older individuals
A rapid decline in circulating lymphocytes is seen early after a stroke (Haeusler et al., 2008; Wang et al., 2017; Juli et al., 2021). At the stroke onset, a decrease in the frequency of circulating T cells was seen in acute ischemic stroke (AIS) patients that negatively correlated with infarct volume and NIHSS on day 1 after stroke (Wang et al., 2017). In the same study, although no difference between the frequency of B cells in AIS and controls was observed a negative correlation between B cells percentage and stroke outcomes was evident (age 63.36 ± 13.01 years) (Wang et al., 2017). A recent study showed a decrease in lymphocyte count in patients with leukocytosis was associated with poor NIHSS scores in AIS patients (age < 60 years) (Juli et al., 2021). Circulating CD4+CD28– T cells increased within the first 48 hours after stroke and were associated with an increased risk of recurrent stroke and death (age 75.0 ± 13.5 years) (Nadareishvili et al., 2004). Systemic IL-17 secreting T cells were found to be increased in stroke patients 30 days after stroke and were associated with poor cognitive function (mean age 71.8 ± 14.4 years) (Swardfager et al., 2014). Peripheral Treg proportions declined in the patients within 72 hours of stroke onset (mean age stroke cohort, 65.8± 15.4 years; control cohort, 54.0 ± 10.8 years) (Noh et al., 2018). Additionally, the Treg proportion positively correlated with age but not infarct volume (Noh et al., 2018). Urra et al. (2009) reported a decline in circulating T lymphocytes and Tregs after stroke (mean age 78.9 ± 11.4 years) versus controls (age 65.9 ± 18.6 years). Furthermore, a decrease in circulating B cells was observed after the stroke and was associated with poor stroke outcomes at 3 months (Urra et al., 2009). A study of Dolati et al. (2018) showed that the frequency of CD4+CD25+Tregs reduced whereas the proportion of Th-17 cells was higher in AIS patients (age 67.3 ± 8.9 years) on days 1 and 5 after stroke, suggesting an imbalance in Th17/Treg cells might contribute to stroke pathophysiology. On the contrary, circulating Tregs were shown to be higher in ischemic stroke versus controls (age > 18 years) at admission (Santamaria-Cadavid et al., 2020). Patients with lower Tregs at 48 hours showed reduced circulating IL-10, higher frequency of early neurological deterioration, and risk of infections. Additionally, higher Treg levels during the acute phase of stroke were associated with better functional outcomes at 3 months (Santamaria-Cadavid et al., 2020).
In a study by Mantani et al. (2014) showed that no difference in the circulating CD19+ B cells between controls and stroke cases was observed however, they identified an association between the high level of CD19+CD40+ B cells and a decrease in the risk of stroke incidence. Moreover, higher CD19+CD86+ B cells were associated with increased stroke risk suggesting different B cell subsets may have the opposite impact on stroke risk (Mantani et al., 2014). CD19highIgD+CD38highCD24highCD5high subset has been identified in humans and has shown to have a suppressive role by inducing Foxp3+CD4+CD25+ Tregs (Lemoine et al., 2011). Similarly, B-regulatory cells secreting IL-10 have been identified in rodent models (Yanaba et al., 2008) and have been shown to play a protective role in stroke outcomes in young animals (Offner and Hurn, 2012; Seifert et al., 2018; Ortega et al., 2020). Incidentally, in most studies, an age difference in circulating B and T cells was not reported as only older individuals were included however, the peripheral immune responses to stroke have shown to differ between young and aged humans and rodents (Ritzel et al., 2018; Sykes et al., 2021; Zhang et al., 2022a).
T and B lymphocytes in preclinical stroke in older subjects
Preclinical stroke studies using older animals though limited have shown an increase in brain immune cells infiltration after stroke leading to neuroinflammation (Ritzel et al., 2016; Chauhan et al., 2017; Vogelgesang et al., 2019; Harris et al., 2020; Figure 2). Neuroinflammation contributes to impaired functional recovery in older animals after stroke (Manwani et al., 2011; Buga et al., 2014; Tang et al., 2016; Ritzel et al., 2018). Spleen harbors the largest pool of peripheral immune cells and splenectomy in aged mice reduced infarct size and improved acute functional outcomes (Chauhan et al., 2017). Although, removal of the spleen is not a therapeutic strategy, blocking the egress of lymphocytes from the spleen could reduce brain injury after stroke. Siponimod treatment, an S1PR inhibitor that selectively inhibits lymphocyte egress from the spleen (Arnon and Cyster, 2014), reduced brain T lymphocyte infiltration without improving infarct volume or motor outcomes in middle-aged mice (Vogelgesang et al., 2019). Brain CD4+ T and CD8+ T cell counts were reduced in the middle-aged mice that received the S1PR inhibitor (Vogelgesang et al., 2019). The other source of peripheral immune cells in aged animals after stroke is the gut (Lee et al., 2020). Aged mice receiving a fecal transplant of young microbiome had reduced inflammatory brain IL-17+γδ T cells and improved functional recovery (Lee et al., 2020). In contrast to γδ T cells, T regs cells promote tissue recovery after stroke by reducing neuroinflammation (Liesz et al., 2009). A recent study by Cai et al. (2022) identified CD8+CD122+CD49dloT cells as CD8+regulatory T cells (CD8+TRLs) that promoted neuroprotection after stroke. Post-stroke administration of CD8+TRLs resulted in reduced infarction and improved long-term functional recovery in older animals (Cai et al., 2022).
Brain-infiltrated CD4+ T cells secrete IFN-γ which stimulates monocytes, macrophages, neutrophils, and endothelial cells to release CXCL-10. CXCL-10 in turn stimulates T cells to secrete more IFN-γ and other cytokines (Seifert et al., 2014; Harris et al., 2020). Aged animals had higher circulating and post-stroke brain CXCL-10 levels than young mice. Removal of CD4+ T cells in aged mice after stroke resulted in improved functional recovery (Harris et al., 2020). Additionally, the depletion of CD4+T cells reduced circulating levels of pro-inflammatory cytokines including IFN-γ, CXCL-10, CCL-2, and CXCL-1 (Harris et al., 2020), thus reflecting a detrimental role of T lymphocytes after stroke in aged animals. A recent study demonstrated that 2-hydroxypropyl-β-cyclodextrin, an Food and Drug Administration (FDA)-approved drug that solubilizes and entraps lipophilic substances not only reduced the brain lipid droplet accumulation but also reduced infarct infiltrated B220+ B cells, CD3ε+ T cells and IgA+ antibody-producing plasma cells in the aged mice (Becktel et al., 2022). Furthermore, 2-hydroxypropyl-β-cyclodextrin treatment in older mice attenuated neurodegeneration and improved functional outcomes after stroke (Becktel et al., 2022). After the stroke, BBB is breached, and myelin reactive antigens leak out and are exposed to immune cells in the periphery. The peripheral immune cells recognize them as foreign antigens and mount an auto-aggressive immune response (Frenkel et al., 2003; Dirnagl et al., 2007). Adaptive immunity plays a detrimental role in stroke neuroinflammation and targeting brain-reactive T cells reduced infarct outcomes after stroke (Subramanian et al., 2009; Akiyoshi et al., 2011; Dziennis et al., 2011). Treatment with recombinant T cell receptor ligand 1000 (RTL1000) in middle-aged mice resulted in a decrease in activated microglia/macrophages, and CD3+ T cell infiltration after stroke (Zhu et al., 2015).
B cells are recruited to the brain after an ischemic stroke (Doyle et al., 2015). Loss of B cells has been shown to increase infarct size, impair functional outcomes, and mortality in mice deficient in B cells (Ren et al., 2011). Administration of IL-10-producing Bregs into B cell-deficient and wild-type B cell-sufficient young mice reduced infarct volume but also improved functional outcomes by promoting neurogenesis (Bodhankar et al., 2013, 2014; Ortega et al., 2020). Depletion of B cells by humanized antibody to CD20+ delayed functional recovery and reduced stroke-induced hippocampal neurogenesis (Ortega et al., 2020). Doyle et al. (2015) demonstrated B cells to be responsible for delayed cognitive impairment after stroke. In human postmortem brain tissue, the presence of B cells and auto-reactive IgG staining was observed in some patients with stroke and dementia (Doyle et al., 2015). Higher titers of MBP antibodies are associated with cognitive decline after stroke (Becker et al., 2016). Unfortunately, all these findings were observed in young mice and there is a lack of studies on age stroke models. In our recent study, we reported the presence of the CD11bhi B cells with age and stroke in aged animals (Korf et al., 2022). Furthermore, these cells regulated microglial phagocytosis. However further studies are required to clarify their role in post-stroke recovery.
Conclusion
The world population is growing old and older individuals have a higher risk for cardiovascular diseases including stroke. The aged brain responds differentially to stress or injury as the anatomy and homeostasis of the brain change with aging. Without any neuronal damage, a significant number of individuals suffer from severe cognitive impairment. The immune cells including microglia, T, and B lymphocytes impact the cognition functions with age and stroke. Microglia become dysfunctional with age and contributes to cognitive dysfunction in older individuals. However, depletion or renewal of microglia in older animals does not salvage the deteriorating cognitive functions completely thus supporting the notion although dysfunctional, microglia alone are not the major players. Activated microglia interact with infiltrated T lymphocytes and also negatively influence cognitive functions after stroke. The presence of T and B lymphocytes in the perivascular spaces and brain parenchyma has been documented in humans and rodents. The presence of infiltrated lymphocytes in the brain parenchyma contributes to age-associated cognitive impairment. It is imperative to unveil and understand the mechanisms that are different in aged individuals to develop therapies for age-associated disorders.
Author contributions:JNN and AC drafted the manuscript. AC critically reviewed the manuscript. Both authors have read and approved the manuscript.
Conflicts of interest:The authors declare that they have no competing interests.
C-Editors: Zhao M, Liu WJ, Li CH; T-Editor: Jia Y
Funding:This work was supported by 16POST27490032 American Heart Association post-doctoral fellowship and National Institute of Neurological Disorders and Stroke Exploratory Neuroscience Research Grant R21 NS114836-01A1 (to AC).
References
1. Akiyoshi K, Dziennis S, Palmateer J, Ren X, Vandenbark AA, Offner H, Herson PS, Hurn PD 2011 Recombinant T cell receptor ligands improve outcome after experimental cerebral ischemia. Transl
Stroke Res 2: 404–410.
2. Akwa Y, Hassett DE, Eloranta ML, Sandberg K, Masliah E, Powell H, Whitton JL, Bloom FE, Campbell IL 1998 Transgenic expression of IFN-alpha in the
central nervous system of mice protects against lethal neurotropic viral infection but induces
inflammation and neurodegeneration. J Immunol 161: 5016–5026.
3. Arbaizar-Rovirosa M, Gallizioli M, Pedragosa J, Lozano JJ, Casal C, Pol A, Planas AM 2022
Age-dependent lipid droplet-rich
microglia worsen
stroke outcome in old mice. bioRxiv doi: https://doi.org/10.1101/2022.03.14.484305.
4. Arnon TI, Cyster JG 2014 Blood, sphingosine-1-phosphate and lymphocyte migration dynamics in the spleen. Curr Top Microbiol Immunol 378: 107–128.
5. Baruch K, Ron-Harel N, Gal H, Deczkowska A, Shifrut E, Ndifon W, Mirlas-Neisberg N, Cardon M, Vaknin I, Cahalon L, Berkutzki T, Mattson MP, Gomez-Pinilla F, Friedman N, Schwartz M 2013 CNS-specific immunity at the choroid plexus shifts toward destructive Th2
inflammation in
brain aging. Proc Natl Acad Sci U S A 110:2264–2269.
6. Batterman KV, Cabrera PE, Moore TL, Rosene DL 2021 T cells actively infiltrate the white matter of the aging monkey
brain in relation to increased microglial reactivity and cognitive decline. Front Immunol 12607691
7. Becker KJ, Tanzi P, Zierath D, Buckwalter MS 2016 Antibodies to myelin basic protein are associated with cognitive decline after
stroke. J Neuroimmunol 295-296:9–11.
8. Becktel DA, Zbesko JC, Frye JB, Chung AG, Hayes M, Calderon K, Grover JW, Li A, Garcia FG, Tavera-Garcia MA, Schnellmann RG, Wu HJ, Nguyen TV, Doyle KP 2022 Repeated administration of 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) attenuates the chronic inflammatory response to experimental
stroke. J Neurosci 42:325–348.
9. Berry K, Farias-Itao DS, Grinberg LT, Plowey ED, Schneider JA, Rodriguez RD, Suemoto CK, Buckwalter MS 2021 B and T lymphocyte densities remain stable with
age in human cortex. ASN Neuro 1317590914211018117
10. Beuker C, Schafflick D, Strecker JK, Heming M, Li X, Wolbert J, Schmidt-Pogoda A, Thomas C, Kuhlmann T, Aranda-Pardos I, N AG, Kumar PA, Werner Y, Kilic E, Hermann DM, Wiendl H, Stumm R, Meyer Zu Horste G, Minnerup J 2022
Stroke induces disease-specific myeloid cells in the
brain parenchyma and pia. Nat Commun 13945
11. Bodhankar S, Chen Y, Vandenbark AA, Murphy SJ, Offner H 2013 IL-10-producing B-cells limit CNS
inflammation and infarct volume in experimental
stroke. Metab
Brain Dis 28:375–386.
12. Bodhankar S, Chen Y, Vandenbark AA, Murphy SJ, Offner H 2014 Treatment of experimental
stroke with IL-10-producing B-cells reduces infarct size and peripheral and CNS
inflammation in wild-type B-cell-sufficient mice. Metab
Brain Dis 29:59–73.
13. Breyer RM, Bagdassarian CK, Myers SA, Breyer MD 2001 Prostanoid receptors:subtypes and signaling. Annu Rev Pharmacol Toxicol 41:661–690.
14. Brioschi S, Wang WL, Peng V, Wang M, Shchukina I, Greenberg ZJ, Bando JK, Jaeger N, Czepielewski RS, Swain A, Mogilenko DA, Beatty WL, Bayguinov P, Fitzpatrick JAJ, Schuettpelz LG, Fronick CC, Smirnov I, Kipnis J, Shapiro VS, Wu GF, et al. 2021 Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders. Science 373eabf9277
15. Buga AM, Margaritescu C, Scholz CJ, Radu E, Zelenak C, Popa-Wagner A 2014 Transcriptomics of post-
stroke angiogenesis in the aged
brain. Front Aging Neurosci 644
16. Burns JC, Cotleur B, Walther DM, Bajrami B, Rubino SJ, Wei R, Franchimont N, Cotman SL, Ransohoff RM, Mingueneau M 2020 Differential accumulation of storage bodies with aging defines discrete subsets of
microglia in the healthy
brain. Elife 9:e57495.
17. Cai W, Shi L, Zhao J, Xu F, Dufort C, Ye Q, Yang T, Dai X, Lyu J, Jin C, Pu H, Yu F, Hassan S, Sun Z, Zhang W, Hitchens TK, Shi Y, Thomson AW, Leak RK, Hu X, et al. 2022 Neuroprotection against ischemic
stroke requires a specific class of early responder T cells in mice. J Clin Invest 132:e157678.
18. Campbell IL, Krucker T, Steffensen S, Akwa Y, Powell HC, Lane T, Carr DJ, Gold LH, Henriksen SJ, Siggins GR 1999 Structural and functional neuropathology in transgenic mice with CNS expression of IFN-alpha.
Brain Res 835:46–61.
19. Cantuti-Castelvetri L, Fitzner D, Bosch-Queralt M, Weil MT, Su M, Sen P, Ruhwedel T, Mitkovski M, Trendelenburg G, Lutjohann D, Mobius W, Simons M 2018 Defective cholesterol clearance limits remyelination in the aged
central nervous system. Science 359:684–688.
20. Casolini P, Catalani A, Zuena AR, Angelucci L 2002 Inhibition of COX-2 reduces the
age-dependent increase of hippocampal inflammatory markers, corticosterone secretion, and behavioral impairments in the rat. J Neurosci Res 68:337–343.
21. Chauhan A, Al Mamun A, Spiegel G, Harris N, Zhu L, McCullough LD 2017 Splenectomy protects aged mice from injury after experimental
stroke. Neurobiol Aging 61:102–111.
22. Coelho A, Fernandes HM, Magalhaes R, Moreira PS, Marques P, Soares JM, Amorim L, Portugal-Nunes C, Castanho T, Santos NC, Sousa N 2021 Signatures of white-matter microstructure degradation during aging and its association with cognitive status. Sci Rep 114517
23. Collaborators GBDS 2019 Global, regional , and national burden of
stroke, 1990-2016:a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 18:439–458.
24. Da Mesquita S, Herz J, Wall M, Dykstra T, de Lima KA, Norris GT, Dabhi N, Kennedy T, Baker W, Kipnis J 2021 Aging-associated deficit in CCR7 is linked to worsened glymphatic function,
cognition ,
neuroinflammation , and β-amyloid pathology. Sci Adv 7eabe4601.
25. Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I 2018 Disease-associated
microglia:a universal immune sensor of neurodegeneration. Cell 173:1073–1081.
26. DiNapoli VA, Huber JD, Houser K, Li X, Rosen CL 2008 Early disruptions of the blood-
brain barrier may contribute to exacerbated neuronal damage and prolonged functional recovery following
stroke in aged rats. Neurobiol Aging 29:753–764.
27. Dirnagl U, Klehmet J, Braun JS, Harms H, Meisel C, Ziemssen T, Prass K, Meisel A 2007
Stroke-induced immunodepression:experimental evidence and clinical relevance.
Stroke 38:770–773.
28. Dolati S, Ahmadi M, Khalili M, Taheraghdam AA, Siahmansouri H, Babaloo Z, Aghebati-Maleki L, Jadidi-Niaragh F, Younesi V, Yousefi M 2018 Peripheral Th17/Treg imbalance in elderly patients with ischemic
stroke. Neurol Sci 39:647–654.
29. Doyle KP, Quach LN, Sole M, Axtell RC, Nguyen TV, Soler-Llavina GJ, Jurado S, Han J, Steinman L, Longo FM, Schneider JA, Malenka RC, Buckwalter MS 2015 B-lymphocyte-mediated delayed cognitive impairment following
stroke. J Neurosci 35:2133–2145.
30. Dulken BW, Buckley MT, Navarro Negredo P, Saligrama N, Cayrol R, Leeman DS, George BM, Boutet SC, Hebestreit K, Pluvinage JV, Wyss-Coray T, Weissman IL, Vogel H, Davis MM, Brunet A 2019 Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature 571:205–210.
31. Dziennis S, Mader S, Akiyoshi K, Ren X, Ayala P, Burrows GG, Vandenbark AA, Herson PS, Hurn PD, Offner HA 2011 Therapy with recombinant T-cell receptor ligand reduces infarct size and infiltrating inflammatory cells in
brain after
middle cerebral artery occlusion in mice. Metab
Brain Dis 26:123–133.
32. Ellwardt E, Walsh JT, Kipnis J, Zipp F 2016 Understanding the role of T cells in CNS homeostasis. Trends Immunol 37:154–165.
33. Elmore MR, Najafi AR, Koike MA, Dagher NN, Spangenberg EE, Rice RA, Kitazawa M, Matusow B, Nguyen H, West BL, Green KN 2014 Colony-stimulating factor 1 receptor signaling is necessary for
microglia viability, unmasking a
microglia progenitor cell in the adult
brain. Neuron 82:380–397.
34. Elmore MRP, Hohsfield LA, Kramar EA, Soreq L, Lee RJ, Pham ST, Najafi AR, Spangenberg EE, Wood MA, West BL, Green KN 2018 Replacement of
microglia in the aged
brain reverses cognitive, synaptic , and neuronal deficits in mice. Aging Cell 17:e12832.
35. Etherton MR, Wu O, Giese AK, Lauer A, Boulouis G, Mills B, Cloonan L, Donahue KL, Copen W, Schaefer P, Rost NS 2019 White matter integrity and early outcomes after acute ischemic
stroke. Transl
Stroke Res 10:630–638.
36. Faheem H, Mansour A, Elkordy A, Rashad S, Shebl M, Madi M, Elwy S, Niizuma K, Tominaga T 2019 Neuroprotective effects of minocycline and progesterone on
white matter injury after focal cerebral ischemia. J Clin Neurosci 64:206–213.
37. Faizy TD, Thaler C, Broocks G, Flottmann F, Leischner H, Kniep H, Nawabi J, Schon G, Stellmann JP, Kemmling A, Reddy R, Heit JJ, Fiehler J, Kumar D, Hanning U 2020 The myelin water fraction serves as a marker for
age-related myelin alterations in the cerebral white matter - A multiparametric MRI aging study. Front Neurosci 14136
38. Fang W, Zhai X, Han D, Xiong X, Wang T, Zeng X, He S, Liu R, Miyata M, Xu B, Zhao H 2018 CCR2-dependent monocytes/macrophages exacerbate acute
brain injury but promote functional recovery after ischemic
stroke in mice. Theranostics 8:3530–3543.
39. Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, Moran AE, Sacco RL, Anderson L, Truelsen T, O’Donnell M, Venketasubramanian N, Barker-Collo S, Lawes CM, Wang W, Shinohara Y, Witt E, Ezzati M, Naghavi M, Murray C, et al. 2014 Global and regional burden of
stroke during 1990-2010:findings from the Global Burden of Disease Study 2010. Lancet 383:245–254.
40. Fitzpatrick Z, Frazer G, Ferro A, Clare S, Bouladoux N, Ferdinand J, Tuong ZK, Negro-Demontel ML, Kumar N, Suchanek O, Tajsic T, Harcourt K, Scott K, Bashford-Rogers R, Helmy A, Reich DS, Belkaid Y, Lawley TD, McGavern DB, Clatworthy MR 2020 Gut-educated IgA plasma cells defend the meningeal venous sinuses. Nature 587:472–476.
41. Fjell AM, Walhovd KB 2010 Structural
brain changes in aging:courses, causes and cognitive consequences. Rev Neurosci 21:187–221.
42. Foley P 2010 Lipids in Alzheimer’s disease:A century-old story. Biochim Biophys Acta 1801:750–753.
43. Frenkel D, Huang Z, Maron R, Koldzic DN, Hancock WW, Moskowitz MA, Weiner HL 2003 Nasal vaccination with myelin oligodendrocyte glycoprotein reduces
stroke size by inducing IL-10-producing CD4+T cells. J Immunol 171:6549–6555.
44. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Lassmann H 2009 The relation between
inflammation and neurodegeneration in multiple sclerosis brains.
Brain 132:1175–1189.
45. Fu JH, Lu CZ, Hong Z, Dong Q, Luo Y, Wong KS 2005 Extent of white matter lesions is related to acute subcortical infarcts and predicts further
stroke risk in patients with first ever ischaemic
stroke. J Neurol Neurosurg Psychiatry 76:793–796.
46. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Judd SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid DJ, Marcus GM, et al. 2014 Executive summary:heart disease and
stroke statistics--2014 update:a report from the American Heart Association. Circulation 129:399–410.
47. Good-Jacobson KL, Song E, Anderson S, Sharpe AH, Shlomchik MJ 2012 CD80 expression on B cells regulates murine T follicular helper development, germinal center B cell survival, and plasma cell generation. J Immunol 188:4217–4225.
48. Groh J, Knöpper K, Arampatzi P, Yuan X, Lößlein L, Saliba AE, Kastenmüller W, Martini R 2021 Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline. Nature Aging 1:357–367.
49. Haeusler KG, Schmidt WU, Fohring F, Meisel C, Helms T, Jungehulsing GJ, Nolte CH, Schmolke K, Wegner B, Meisel A, Dirnagl U, Villringer A, Volk HD 2008 Cellular immunodepression preceding infectious complications after acute ischemic
stroke in humans. Cerebrovasc Dis 25:50–58.
50. Hao Y, O’Neill P, Naradikian MS, Scholz JL, Cancro MP 2011 A B-cell subset uniquely responsive to innate stimuli accumulates in aged mice. Blood 118:1294–1304.
51. Harada CN, Natelson Love MC, Triebel KL 2013 Normal cognitive aging. Clin Geriatr Med 29:737–752.
52. Harris NM, Roy-O’Reilly M, Ritzel RM, Holmes A, Sansing LH, O’Keefe LM, McCullough LD, Chauhan A 2020 Depletion of CD4 T cells provides therapeutic benefits in aged mice after ischemic
stroke. Exp Neurol 326113202
53. Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC, Means TK, El Khoury J 2013 The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16:1896–1905.
54. Hong S, Giese AK, Schirmer MD, Bonkhoff AK, Bretzner M, Rist P, Dalca AV, Regenhardt RW, Etherton MR, Donahue KL, Nardin M, Mocking SJT, McIntosh EC, Attia J, Benavente OR, Cole JW, Donatti A, Griessenauer CJ, Heitsch L, Holmegaard L, et al. 2021 Excessive white matter hyperintensity increases susceptibility to poor functional outcomes after acute ischemic
stroke. Front Neurol 12700616
55. Howell OW, Reeves CA, Nicholas R, Carassiti D, Radotra B, Gentleman SM, Serafini B, Aloisi F, Roncaroli F, Magliozzi R, Reynolds R 2011 Meningeal
inflammation is widespread and linked to cortical pathology in multiple sclerosis.
Brain 134:2755–2771.
56. Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, Chen J 2015 Microglial and macrophage polarization-new prospects for
brain repair. Nat Rev Neurol 11:56–64.
57. Ito M, Muramatsu R, Kato Y, Sharma B, Uyeda A, Tanabe S, Fujimura H, Kidoya H, Takakura N, Kawahara Y, Takao M, Mochizuki H, Fukamizu A, Yamashita T 2021
Age-dependent decline in remyelination capacity is mediated by apelin–APJ signaling. Nature Aging 1:284–294.
58. Jain RW, Yong VW 2022 B cells in
central nervous system disease:diversity, locations and pathophysiology. Nat Rev Immunol 22:513–524.
59. Jaul E, Barron J 2017
Age-related diseases and clinical and public health implications for the 85 years old and over population. Front Public Health 5335
60. Jiang L, Mu H, Xu F, Xie D, Su W, Xu J, Sun Z, Liu S, Luo J, Shi Y, Leak RK, Wechsler LR, Chen J, Hu X 2020 Transcriptomic and functional studies reveal undermined chemotactic and angiostimulatory properties of aged
microglia during
stroke recovery. J Cereb Blood Flow Metab 40S81–S97.
61. Juli C, Heryaman H, Nazir A, Ang ET, Defi IR, Gamayani U, Atik N 2021 The lymphocyte depletion in patients with acute ischemic
stroke associated with poor neurologic outcome. Int J Gen Med 14:1843–1851.
62. Juraska JM, Lowry NC 2012 Neuroanatomical changes associated with cognitive aging. Curr Top Behav Neurosci 10:137–162.
63. Kalafatakis I, Karagogeos D 2021 Oligodendrocytes and
microglia:key players in myelin development, damage and repair. Biomolecules 111058
64. Kalamakis G, Brüne D, Ravichandran S, Bolz J, Fan W, Ziebell F, Stiehl T, Catalá-Martinez F, Kupke J, Zhao S, Llorens-Bobadilla E, Bauer K, Limpert S, Berger B, Christen U, Schmezer P, Mallm JP, Berninger B, Anders S, Del Sol A, et al. 2019 Quiescence modulates stem cell maintenance and regenerative capacity in the aging
brain. Cell 176:1407–1419.
65. Kharlamov A, Kharlamov E, Armstrong DM 2000
Age-dependent increase in infarct volume following photochemically induced cerebral infarction:putative role of astroglia. J Gerontol A Biol Sci Med Sci 55B135–141.
66. Kohama SG, Rosene DL, Sherman LS 2012
Age-related changes in human and non-human primate white matter:from myelination disturbances to cognitive decline.
Age (Dordr) 34:1093–1110.
67. Korf JM, Honarpisheh P, Mohan EC, Banerjee A, Blasco-Conesa MP, Honarpisheh P, Guzman GU, Khan R, Ganesh BP, Hazen AL, Lee J, Kumar A, McCullough LD, Chauhan A 2022 CD11b(high) B cells increase after
stroke and regulate
microglia. J Immunol 209:288–300.
68. Korin B, Ben-Shaanan TL, Schiller M, Dubovik T, Azulay-Debby H, Boshnak NT, Koren T, Rolls A 2017 High-dimensional, single-cell characterization of the
brain’s immune compartment. Nat Neurosci 20:1300–1309.
69. Kowal P, Goodkind D, He W 2016 An Aging World 2015, International Population Reports. Washington DC U S. Government Printing Office.
70. Lee J, d’Aigle J, Atadja L, Quaicoe V, Honarpisheh P, Ganesh BP, Hassan A, Graf J, Petrosino J, Putluri N, Zhu L, Durgan DJ, Bryan RM Jr, McCullough LD, Venna VR 2020 Gut microbiota-derived short-chain fatty acids promote poststroke recovery in aged mice. Circ Res 127:453–465.
71. Lemoine S, Morva A, Youinou P, Jamin C 2011 Human T cells induce their own regulation through activation of B cells. J Autoimmun 36:228–238.
72. Li L, Simoni M, Kuker W, Schulz UG, Christie S, Wilcock GK, Rothwell PM 2013 Population-based case-control study of white matter changes on
brain imaging in transient ischemic attack and ischemic
stroke.
Stroke 44:3063–3070.
73. Li YQ, Sun L, Li J 2019 Macropinocytosis-dependent endocytosis of Japanese flounder IgM(+) B cells and its regulation by CD22. Fish Shellfish Immunol 84:138–147.
74. Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, Giese T, Veltkamp R 2009 Regulatory T cells are key cerebroprotective immunomodulators in acute experimental
stroke. Nat Med 15:192–199.
75. Liu T, Zhang L, Joo D, Sun SC 2017 NF-kappaB signaling in
inflammation. Signal Transduct Target Ther 2.
76. Liu X, Jiang X, Liu R, Wang L, Qian T, Zheng Y, Deng Y, Huang E, Xu F, Wang JY, Chu Y 2015 B cells expressing CD11b effectively inhibit CD4+T-cell responses and ameliorate experimental autoimmune hepatitis in mice. Hepatology 62:1563–1575.
77. Luan W, Qi X, Liang F, Zhang X, Jin Z, Shi L, Luo B, Dai X 2021
Microglia impede oligodendrocyte generation in aged
brain. J Inflamm Res 14:6813–6831.
78. Ma S, Wang C, Mao X, Hao Y 2019 B cell dysfunction associated with aging and autoimmune diseases. Front Immunol 10318
79. Machado-Santos J, Saji E, Troscher AR, Paunovic M, Liblau R, Gabriely G, Bien CG, Bauer J, Lassmann H 2018 The compartmentalized inflammatory response in the multiple sclerosis
brain is composed of tissue-resident CD8+
T lymphocytes and B cells.
Brain 141:2066–2082.
80. Macrez R, Ali C, Toutirais O, Le Mauff B, Defer G, Dirnagl U, Vivien D 2011
Stroke and the immune system:from pathophysiology to new therapeutic strategies. Lancet Neurol 10:471–480.
81. Mantani PT, Ljungcrantz I, Andersson L, Alm R, Hedblad B, Bjorkbacka H, Nilsson J, Fredrikson GN 2014 Circulating CD40+and CD86+B cell subsets demonstrate opposing associations with risk of
stroke. Arterioscler Thromb Vasc Biol 34:211–218.
82. Manwani B, Liu F, Xu Y, Persky R, Li J, McCullough LD 2011 Functional recovery in aging mice after experimental
stroke.
Brain Behav Immun 25:1689–1700.
83. Marchetti L, Engelhardt B 2020 Immune cell trafficking across the blood-
brain barrier in the absence and presence of
neuroinflammation. Vasc Biol 2H1–18.
84. Marin MA, Carmichael ST 2018
Stroke in CNS white matter:Models and mechanisms. Neurosci Lett 684:193–199.
85. Marino Lee S, Hudobenko J, McCullough LD, Chauhan A 2021
Microglia depletion increase
brain injury after acute ischemic
stroke in aged mice. Exp Neurol 336113530
86. Marschallinger J, Iram T, Zardeneta M, Lee SE, Lehallier B, Haney MS, Pluvinage JV, Mathur V, Hahn O, Morgens DW, Kim J, Tevini J, Felder TK, Wolinski H, Bertozzi CR, Bassik MC, Aigner L, Wyss-Coray T 2020 Lipid-droplet-accumulating
microglia represent a dysfunctional and proinflammatory state in the aging
brain. Nat Neurosci 23:194–208.
87. Minhas PS, Latif-Hernandez A, McReynolds MR, Durairaj AS, Wang Q, Rubin A, Joshi AU, He JQ, Gauba E, Liu L, Wang C, Linde M, Sugiura Y, Moon PK, Majeti R, Suematsu M, Mochly-Rosen D, Weissman IL, Longo FM, Rabinowitz JD, et al. 2021 Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature 590:122–128.
88. Mohebiany AN, Ramphal NS, Karram K, Di Liberto G, Novkovic T, Klein M, Marini F, Kreutzfeldt M, Hartner F, Lacher SM, Bopp T, Mittmann T, Merkler D, Waisman A 2020 Microglial A20 protects the
brain from CD8 T-cell-mediated immunopathology. Cell Rep 30:1585–1597.
89. Moreno-Valladares M, Moreno-Cugnon L, Silva TM, Garces JP, Saenz-Antonanzas A, Alvarez-Satta M, Matheu A 2020a CD8(+) T cells are increased in the subventricular zone with physiological and pathological aging. Aging Cell 19:e13198.
90. Moreno-Valladares M, Silva TM, Garces JP, Saenz-Antonanzas A, Moreno-Cugnon L, Alvarez-Satta M, Matheu A 2020b CD8(+) T cells are present at low levels in the white matter with physiological and pathological aging. Aging (Albany NY) 12:18928–18941.
91. Nadareishvili ZG, Li H, Wright V, Maric D, Warach S, Hallenbeck JM, Dambrosia J, Barker JL, Baird AE 2004 Elevated pro-inflammatory CD4+CD28- lymphocytes and
stroke recurrence and death. Neurology 63:1446–1451.
92. Nakanishi H 2020 Microglial cathepsin B as a key driver of inflammatory
brain diseases and
brain aging. Neural Regen Res 15:25–29.
93. Neumann B, Segel M, Chalut KJ, Franklin RJ 2019 Remyelination and ageing:Reversing the ravages of time. Mult Scler 25:1835–1841.
94. Ni J, Wu Z, Stoka V, Meng J, Hayashi Y, Peters C, Qing H, Turk V, Nakanishi H 2019 Increased expression and altered subcellular distribution of cathepsin B in
microglia induce cognitive impairment through oxidative stress and inflammatory response in mice. Aging Cell 18:e12856.
95. Nitschke L, Carsetti R, Ocker B, Kohler G, Lamers MC 1997 CD22 is a negative regulator of B-cell receptor signalling. Curr Biol 7:133–143.
96. Noh MY, Lee WM, Lee SJ, Kim HY, Kim SH, Kim YS 2018 Regulatory T cells increase after treatment with poly (ADP-ribose) polymerase-1 inhibitor in ischemic
stroke patients. Int Immunopharmacol 60:104–110.
97. O’Neil SM, Witcher KG, McKim DB, Godbout JP 2018 Forced turnover of aged
microglia induces an intermediate phenotype but does not rebalance CNS environmental cues driving priming to immune challenge. Acta Neuropathol Commun 6129
98. Offner H, Hurn PD 2012 A novel hypothesis:regulatory
B lymphocytes shape outcome from experimental
stroke. Transl
Stroke Res 3:324–330.
99. Ortega SB, Torres VO, Latchney SE, Whoolery CW, Noorbhai IZ, Poinsatte K, Selvaraj UM, Benson MA, Meeuwissen AJM, Plautz EJ, Kong X, Ramirez DM, Ajay AD, Meeks JP, Goldberg MP, Monson NL, Eisch AJ, Stowe AM 2020 B cells migrate into remote
brain areas and support neurogenesis and functional recovery after focal
stroke in mice. Proc Natl Acad Sci U S A 117:4983–4993.
100. Perry VH, Matyszak MK, Fearn S 1993 Altered antigen expression of
microglia in the aged rodent CNS. Glia 7:60–67.
101. Pessac B, Godin I, Alliot F 2001
Microglia:origin and development. Bull Acad Natl Med 185337–346
102. Peters A, Kemper T 2012 A review of the structural alterations in the cerebral hemispheres of the aging rhesus monkey. Neurobiol Aging 33:2357–2372.
103. Pluvinage JV, Haney MS, Smith BAH, Sun J, Iram T, Bonanno L, Li L, Lee DP, Morgens DW, Yang AC, Shuken SR, Gate D, Scott M, Khatri P, Luo J, Bertozzi CR, Bassik MC, Wyss-Coray T 2019 CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature 568:187–192.
104. Prasad R 1983 Immunoglobulin levels in serum and cerebrospinal fluid in certain viral infections of the
central nervous system. J Infect Dis 148607
105. Qian T, Hong J, Wang L, Wang Z, Lu Z, Li Y, Liu R, Chu Y 2019 Regulation of CD11b by HIF-1alpha and the STAT3 signaling pathway contributes to the immunosuppressive function of B cells in inflammatory bowel disease. Mol Immunol 111:162–171.
106. Rawji KS, Young AMH, Ghosh T, Michaels NJ, Mirzaei R, Kappen J, Kolehmainen KL, Alaeiilkhchi N, Lozinski B, Mishra MK, Pu A, Tang W, Zein S, Kaushik DK, Keough MB, Plemel JR, Calvert F, Knights AJ, Gaffney DJ, Tetzlaff W, et al. 2020 Niacin-mediated rejuvenation of macrophage/
microglia enhances remyelination of the aging
central nervous system. Acta Neuropathol 139:893–909.
107. Ren X, Akiyoshi K, Dziennis S, Vandenbark AA, Herson PS, Hurn PD, Offner H 2011 Regulatory B cells limit CNS
inflammation and neurologic deficits in murine experimental
stroke. J Neurosci 31:8556–8563.
108. Ritzel RM, Patel AR, Pan S, Crapser J, Hammond M, Jellison E, McCullough LD 2015
Age- and location-related changes in microglial function. Neurobiol Aging 36:2153–2163.
109. Ritzel RM, Crapser J, Patel AR, Verma R, Grenier JM, Chauhan A, Jellison ER, McCullough LD 2016
Age-associated resident memory CD8 T cells in the
central nervous system are primed to potentiate
inflammation after ischemic
brain injury. J Immunol 196:3318–3330.
110. Ritzel RM, Lai YJ, Crapser JD, Patel AR, Schrecengost A, Grenier JM, Mancini NS, Patrizz A, Jellison ER, Morales-Scheihing D, Venna VR, Kofler JK, Liu F, Verma R, McCullough LD 2018 Aging alters the immunological response to ischemic
stroke. Acta Neuropathol 136:89–110.
111. Rojas OL, Sellrie K, Bischof A, Kim K, Ramesh A, Dandekar R, Greenfield AL, Schubert RD, Bisanz JE, Vistnes S, Khaleghi K, Landefeld J, Kirkish G, Liesche-Starnecker F, Ramaglia V, Singh S, Tran EB, Barba P, Zorn K, Oechtering J, et al. 2020 Gut microbiota-specific IgA+B cells traffic to the CNS in active multiple sclerosis. Sci Immunol 5eabc7191
112. Rosenzweig S, Carmichael ST 2013
Age-dependent exacerbation of white matter
stroke outcomes:a role for oxidative damage and inflammatory mediators.
Stroke 44:2579–2586.
113. Rubtsov AV, Rubtsova K, Fischer A, Meehan RT, Gillis JZ, Kappler JW, Marrack P 2011 Toll-like receptor 7 (TLR7)-driven accumulation of a novel CD11c(+) B-cell population is important for the development of autoimmunity. Blood 118:1305–1315.
114. Rubtsova K, Rubtsov AV, Cancro MP, Marrack P 2015
Age-associated B cells:A T-bet-dependent effector with roles in protective and pathogenic immunity. J Immunol 195:1933–1937.
115. Rustenhoven J, Drieu A, Mamuladze T, de Lima KA, Dykstra T, Wall M, Papadopoulos Z, Kanamori M, Salvador AF, Baker W, Lemieux M, Da Mesquita S, Cugurra A, Fitzpatrick J, Sviben S, Kossina R, Bayguinov P, Townsend RR, Zhang Q, Erdmann-Gilmore P, et al. 2021 Functional characterization of the dural sinuses as a neuroimmune interface. Cell 184:1000–1016.
116. Safaiyan S, Kannaiyan N, Snaidero N, Brioschi S, Biber K, Yona S, Edinger AL, Jung S, Rossner MJ, Simons M 2016
Age-related myelin degradation burdens the clearance function of
microglia during aging. Nat Neurosci 19:995–998.
117. Sams EC 2021 Oligodendrocytes in the aging
brain. Neuronal Signal 5NS20210008
118. Sanderson RD, Lalor P, Bernfield M 1989
B lymphocytes express and lose syndecan at specific stages of differentiation. Cell Regul 1:27–35.
119. Santamaria-Cadavid M, Rodriguez-Castro E, Rodriguez-Yanez M, Arias-Rivas S, Lopez-Dequidt I, Perez-Mato M, Rodriguez-Perez M, Lopez-Loureiro I, Hervella P, Campos F, Castillo J, Iglesias-Rey R, Sobrino T 2020 Regulatory T cells participate in the recovery of ischemic
stroke patients. BMC Neurol 2068
120. Schafflick D, Wolbert J, Heming M, Thomas C, Hartlehnert M, Borsch AL, Ricci A, Martin-Salamanca S, Li X, Lu IN, Pawlak M, Minnerup J, Strecker JK, Seidenbecher T, Meuth SG, Hidalgo A, Liesz A, Wiendl H, Meyer Zu Horste G 2021 Single-cell profiling of CNS border compartment leukocytes reveals that B cells and their progenitors reside in non-diseased meninges. Nat Neurosci 24:1225–1234.
121. Schetters STT, Gomez-Nicola D, Garcia-Vallejo JJ, Van Kooyk Y 2017
Neuroinflammation:
microglia and T cells get ready to tango. Front Immunol 81905
122. Schittenhelm L, Hilkens CM, Morrison VL 2017 beta2 integrins as regulators of dendritic cell, monocyte , and macrophage function. Front Immunol 81866
123. Schneider E, Rissiek A, Winzer R, Puig B, Rissiek B, Haag F, Mittrucker HW, Magnus T, Tolosa E 2019 Generation and function of non-cell-bound CD73 in
inflammation. Front Immunol 101729
124. Seifert HA, Collier LA, Chapman CB, Benkovic SA, Willing AE, Pennypacker KR 2014 Pro-inflammatory interferon gamma signaling is directly associated with
stroke induced neurodegeneration. J Neuroimmune Pharmacol 9:679–689.
125. Seifert HA, Vandenbark AA, Offner H 2018 Regulatory B cells in experimental
stroke. Immunology 154:169–177.
126. Sheffield LG, Berman NE 1998 Microglial expression of MHC class II increases in normal aging of nonhuman primates. Neurobiol Aging 19:47–55.
127. Shi L, Rocha M, Zhang W, Jiang M, Li S, Ye Q, Hassan SH, Liu L, Adair MN, Xu J, Luo J, Hu X, Wechsler LR, Chen J, Shi Y 2020 Genome-wide transcriptomic analysis of
microglia reveals impaired responses in aged mice after cerebral ischemia. J Cereb Blood Flow Metab 40S49–66.
128. Shields S, Gilson J, Blakemore W, Franklin R 2000 Remyelination occurs as extensively but more slowly in old rats compared to young rats following fliotoxin-induced CNS demyelination. Glia 29102
129. Smolders J, Heutinck KM, Fransen NL, Remmerswaal EBM, Hombrink P, Ten Berge IJM, van Lier RAW, Huitinga I, Hamann J 2018 Tissue-resident memory T cells populate the human
brain. Nat Commun 94593
130. Soreq L, Consortium UKBE, North American
Brain Expression C, Rose J, Soreq E, Hardy J, Trabzuni D, Cookson MR, Smith C, Ryten M, Patani R, Ule J 2017 Major shifts in glial regional identity are a transcriptional hallmark of human
brain aging. Cell Rep 18:557–570.
131. Spangenberg E, Severson PL, Hohsfield LA, Crapser J, Zhang J, Burton EA, Zhang Y, Spevak W, Lin J, Phan NY, Habets G, Rymar A, Tsang G, Walters J, Nespi M, Singh P, Broome S, Ibrahim P, Zhang C, Bollag G, et al. 2019 Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model. Nat Commun 103758
132. Spangenberg EE, Lee RJ, Najafi AR, Rice RA, Elmore MR, Blurton-Jones M, West BL, Green KN 2016 Eliminating
microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-beta pathology.
Brain 139:1265–1281.
133. Spitzer SO, Sitnikov S, Kamen Y, Evans KA, Kronenberg-Versteeg D, Dietmann S, de Faria O Jr, Agathou S, Karadottir RT 2019 Oligodendrocyte progenitor cells become regionally diverse and heterogeneous with
age. Neuron 101:459–471.
134. Stadler J, Schurr H, Doyle D, Garmo L, Srinageshwar B, Spencer MR, Petersen RB, Dunbar GL, Rossignol J 2022 Temporal profile of reactive astrocytes after ischemic
stroke in rats. Neuroglia 3:99–111.
135. Stanley ER, Chitu V 2014 CSF-1 receptor signaling in myeloid cells. Cold Spring Harb Perspect Biol 6.
136. Streit WJ, Sparks DL 1997 Activation of
microglia in the brains of humans with heart disease and hypercholesterolemic rabbits. J Mol Med (Berl) 75:130–138.
137. Streit WJ, Xue QS, Tischer J, Bechmann I 2014 Microglial pathology. Acta Neuropathol Commun 2142
138. Subramanian S, Zhang B, Kosaka Y, Burrows GG, Grafe MR, Vandenbark AA, Hurn PD, Offner H 2009 Recombinant T cell receptor ligand treats experimental
stroke.
Stroke 40:2539–2545.
139. Suenaga J, Hu X, Pu H, Shi Y, Hassan SH, Xu M, Leak RK, Stetler RA, Gao Y, Chen J 2015
White matter injury and
microglia/macrophage polarization are strongly linked with
age-related long-term deficits in neurological function after
stroke. Exp Neurol 272:109–119.
140. Sutherland GR, Dix GA, Auer RN 1996 Effect of
age in rodent models of focal and forebrain ischemia.
Stroke 27:1663–1667.
141. Swardfager W, Herrmann N, Andreazza AC, Swartz RH, Khan MM, Black SE, Lanctot KL 2014 Poststroke neuropsychiatric symptoms:relationships with IL-17 and oxidative stress. Biomed Res Int 2014 245210.
142. Sykes GP, Kamtchum-Tatuene J, Falcione S, Zehnder S, Munsterman D, Stamova B, Ander BP, Sharp FR, Jickling G 2021 Aging immune system in acute ischemic
stroke:a transcriptomic analysis.
Stroke 52:1355–1361.
143. Szalay G, Martinecz B, Lénárt N, Környei Z, Orsolits B, Judák L, Császár E, Fekete R, West BL, Katona G, Rózsa B, Dénes Á 2016
Microglia protect against
brain injury and their selective elimination dysregulates neuronal network activity after
stroke. Nat Commun 711499
144. Tan Z, Turner RC, Leon RL, Li X, Hongpaisan J, Zheng W, Logsdon AF, Naser ZJ, Alkon DL, Rosen CL, Huber JD 2013 Bryostatin improves survival and reduces ischemic
brain injury in aged rats after acute ischemic
stroke.
Stroke 44:3490–3497.
145. Tang Y, Wang L, Wang J, Lin X, Wang Y, Jin K, Yang GY 2016 Ischemia-induced angiogenesis is attenuated in aged rats. Aging Dis 7:326–335.
146. Taylor RA, Sansing LH 2013 Microglial responses after ischemic
stroke and intracerebral hemorrhage. Clin Dev Immunol 2013 746068.
147. Tilstra JS, Clauson CL, Niedernhofer LJ, Robbins PD 2011 NF-kappaB in aging and disease. Aging Dis 2:449–465.
148. Urban SL, Jensen IJ, Shan Q, Pewe LL, Xue HH, Badovinac VP, Harty JT 2020 Peripherally induced
brain tissue-resident memory CD8(+) T cells mediate protection against CNS infection. Nat Immunol 21:938–949.
149. Urra X, Cervera A, Villamor N, Planas AM, Chamorro A 2009 Harms and benefits of lymphocyte subpopulations in patients with acute
stroke. Neuroscience 158:1174–1183.
150. Vaughan DW, Peters A 1974 Neuroglial cells in the cerebral cortex of rats from young adulthood to old
age:an electron microscope study. J Neurocytol 3:405–429.
151. Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, et al. 2011 The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477:90–94.
152. Voet S, Mc Guire C, Hagemeyer N, Martens A, Schroeder A, Wieghofer P, Daems C, Staszewski O, Vande Walle L, Jordao MJC, Sze M, Vikkula HK, Demeestere D, Van Imschoot G, Scott CL, Hoste E, Gonçalves A, Guilliams M, Lippens S, Libert C, et al. 2018 A20 critically controls
microglia activation and inhibits inflammasome-dependent
neuroinflammation. Nat Commun 92036
153. Vogelgesang A, Domanska G, Ruhnau J, Dressel A, Kirsch M, Schulze J 2019 Siponimod (BAF312) treatment reduces
brain infiltration but not lesion volume in middle-aged mice in experimental
stroke.
Stroke 50:1224–1231.
154. Walter J, Keiner S, Witte OW, Redecker C 2010 Differential
stroke-induced proliferative response of distinct precursor cell subpopulations in the young and aged dentate gyrus. Neuroscience 169:1279–1286.
155. Wang G, Jiang X, Pu H, Zhang W, An C, Hu X, Liou AK, Leak RK, Gao Y, Chen J 2013 Scriptaid, a novel histone deacetylase inhibitor, protects against traumatic
brain injury via modulation of PTEN and AKT pathway :scriptaid protects against TBI via AKT. Neurotherapeutics 10:124–142.
156. Wang Y, Liu J, Wang X, Liu Z, Li F, Chen F, Geng X, Ji Z, Du H, Hu X 2017 Frequencies of circulating B- and T-lymphocytes as indicators for
stroke outcomes. Neuropsychiatr Dis Treat 13:2509–2518.
157. Wu D, Meydani SN 2004 Mechanism of
age-associated up-regulation in macrophage PGE2 synthesis.
Brain Behav Immun 18:487–494.
158. Wu YC, Kipling D, Dunn-Walters DK 2011 The relationship between CD27 negative and positive B cell populations in human peripheral blood. Front Immunol 281
159. Xiao JY, Xiong BR, Zhang W, Zhou WC, Yang H, Gao F, Xiang HB, Manyande A, Tian XB, Tian YK 2018 PGE2-EP3 signaling exacerbates hippocampus-dependent cognitive impairment after laparotomy by reducing expression levels of hippocampal synaptic plasticity-related proteins in aged mice. CNS Neurosci Ther 24:917–929.
160. Yanaba K, Bouaziz JD, Haas KM, Poe JC, Fujimoto M, Tedder TF 2008 A regulatory B cell subset with a unique CD1dhiCD5+phenotype controls T cell-dependent inflammatory responses. Immunity 28:639–650.
161. Yang AC, Stevens MY, Chen MB, Lee DP, Stähli D, Gate D, Contrepois K, Chen W, Iram T, Zhang L, Vest RT, Chaney A, Lehallier B, Olsson N, du Bois H, Hsieh R, Cropper HC, Berdnik D, Li L, Wang EY, et al. 2020 Physiological blood-
brain transport is impaired with
age by a shift in transcytosis. Nature 583:425–430.
162. Yanguas-Casas N, Crespo-Castrillo A, Arevalo MA, Garcia-Segura LM 2020 Aging and sex:Impact on
microglia phagocytosis. Aging Cell 19:e13182.
163. Yegla B, Boles J, Kumar A, Foster TC 2021 Partial microglial depletion is associated with impaired hippocampal synaptic and cognitive function in young and aged rats. Glia 69:1494–1514.
164. Zhang H, Guan J, Lee H, Wu C, Dong K, Liu Z, Cui L, Song H, Ding Y, Meng R 2022a Immunocytes rapid responses post-ischemic
stroke in peripheral blood in patients with different ages. Front Neurol 13887526.
165. Zhang X, Wang R, Chen H, Jin C, Jin Z, Lu J, Xu L, Lu Y, Zhang J, Shi L 2022b Aged
microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches. Immun Ageing 1934
166. Zhao J, Bi W, Xiao S, Lan X, Cheng X, Zhang J, Lu D, Wei W, Wang Y, Li H, Fu Y, Zhu L 2019
Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Sci Rep 95790
167. Zhou L, Kong G, Palmisano I, Cencioni MT, Danzi M, De Virgiliis F, Chadwick JS, Crawford G, Yu Z, De Winter F, Lemmon V, Bixby J, Puttagunta R, Verhaagen J, Pospori C, Lo Celso C, Strid J, Botto M, Di Giovanni S 2022 Reversible CD8 T cell-neuron cross-talk causes aging-dependent neuronal regenerative decline. Science 376eabd5926
168. Zhu W, Dotson AL, Libal NL, Lapato AS, Bodhankar S, Offner H, Alkayed NJ 2015 Recombinant T-cell receptor ligand RTL1000 limits
inflammation and decreases infarct size after experimental ischemic
stroke in middle-aged mice. Neuroscience 288:112–119.
