INTRODUCTION
Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and inflammation is implicated in the pathogenesis of myocardial infarction (MI), atherosclerosis, cardiomyopathy, hypertension, and heart failure (HF)[1]. The macrophages and inflammasomes are the main contributors to the inflammatory response[2,3]. Therefore, an in-depth exploration of the mechanisms underlying the activation of macrophages and inflammasomes will provide new therapeutic targets for the treatment of CVDs.
OVERVIEW OF MACROPHAGES
Biological characteristics of macrophages
Macrophages are immune cells present in all tissues from the earliest stage of growth and are involved in the progression of diseases by uptaking and digesting cellular components and secreting cytokines[4]. Macrophage polarization is a process to allow macrophages to change their phenotype in response to environmental stimulation[5]. M0 phenotype is the state that macrophages are at resting condition without any stimulation[6]. When stimulated by lipopolysaccharide (LPS) or interferon-γ (IFN-γ), M0 macrophages become the proinflammatory M1 phenotype[7]. However, in the presence of interleukin-4 (IL-4), IL-13, IL-10, M0 macrophages are polarized into anti-inflammatory M2 phenotype[8–11]. In addition, M1 and M2 macrophages can be transformed into each other. The role of M1 macrophages is to recruit and activate T and B lymphocytes through the production of inflammatory cytokines to eliminate pathogens. When the acute phase of inflammatory response subsides, the anti-inflammatory M2 macrophages become activated to participate in the remodeling of pathological tissues.
Cardiac macrophages
During development, macrophages are derived from the yolk sac, fetal monocyte progenitor cells, and blood monocytes. The distribution of the macrophages varies among different tissues[12]. In the heart, yolk sac–derived macrophages are replaced by fetal monocytes just before birth. After birth, fetal monocytes are replaced by bone marrow–derived monocytes[4]. Macrophages comprise 7% of interstitial cells in the heart and play an impor tant role in cardiac homeostasis. The subsets of cardiac macrophage can be distinguished by their expression of chemokine receptor 2 (CCR2). CCR2− macrophages originate from the embryonic yolk sac, whereas CCR2+ macrophages originate from hematopoietic progenitors. The two subsets of cells have different functions in cardiac development and pathophysiology. CCR2− macrophages are involved in coronary artery development, cardiac remodeling, and regeneration[13]. In the injured neonatal heart, CCR2− macrophages coordinate myocardial regeneration by enhancing cardiomyocyte prolifera tion and hypertrophy. Neonatal mouse hearts display impaired cardiac regeneration in the absence of CCR2− macrophages[14]. However, CCR2+ macrophages are involved in the initiation of inflammation[15] (Figure 1). These studies indicate that different macrophages have distinct functions.
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Figure 1.: Macrophage polarization and phenotype based on CCR2 expression. In the presence of LPS or IFN-γ, M0 macrophages can be polarized into pro-inflammatory M1 macrophages, while under the action of IL-4, IL-13, IL-10, M0 macrophages can polarize into anti-inflammatory M2 macrophages. Based on CCR2 expression, macrophages can be divided into two classes. CCR2− macrophages originate from the embryonic yolk sac and fetal monocytic progenitors and participate in various forms of tissue remodeling. CCR2+ macrophages originate from hematopoietic progenitors and may contribute to the initiation of inflammation.CCR2: Chemokine receptor 2; IFN-γ: Interferon-γ; IL: Interleukin; LPS: Lipopolysaccharide.
Function and regulation of macrophages
Macrophages regulate the immune system by releasing various inflammatory cytokines[16]. Macrophages can also engulf lipoproteins, platelets, red blood cells, and fragments of apoptotic cells[17]. Interestingly, cardiac macrophages maintain cardiac homeostasis by transmitting electrical signals generated by cardiomyocytes and phagocytosing their metabolic waste[18,19]. Therefore, macrophages are critical for the development of CVDs[20,21].
Through pattern recognition receptors (PRRs), macrophages can sense external stimuli via damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs)[22]. The inflammatory signal pathway of macrophages includes transcription factor nuclear factor κB (NF-κB), Janus kinase/signal transducer and activator of transfer (JAK/STAT), activator protein 1 (AP-1) signal pathway, inflammasomes, phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT), and hypoxia-inducible factor (HIF)[5]. The active molecules produced by early proinflammatory macrophages include chemokines (C-C motif chemokine ligand 2 [CCL2], CCL7, chemokine C-X-C motif ligand 12 [CXCL12]) and inflammatory cytokines (IL-6, IL-1 β, tumor necrosis factor-α [TNF-α]), protease, and reactive oxygen species[23]. During the late stage of inflammation, macrophages produce transforming growth factor-β (TGF-β), vascular endothelial growth factor A (VEGF-A), and IL-10[24]. These studies indicate that macrophage functions are regulated by multiple signaling pathways.
THE ROLE OF MACROPHAGES IN CARDIOVASCULAR DISEASES
Macrophages and myocardial infarction
After MI, an inflammatory reaction occurs at the injury site, leading to cardiac remodeling and dysfunction[25]. After the ischemic injury of the adult mouse heart, the number of macrophages increases significantly[26], which limits the repair of the heart through excessive inflammation and subsequent scar formation (Table 1)[32]. Using a model of genetic cardiomyocyte ablation, Lavine et al.[26] demonstrated that the increased number of embryonic-derived resident cardiac macrophages in neonatal heart promotes cardiomyocyte proliferation and angiogenesis. These macrophages also home to the adult heart. However, after injury, these cells are replaced by monocyte-derived macrophages that are pro-inflammatory in nature. Embryonic-derived macrophages can be preserved in the adult heart by inhibiting monocyte recruitment. These findings suggest that embryonic-derived macrophages mediate cardiac recovery[33]. Thus, macrophages of different origins play different roles during the course of MI.
Table 1. -
Effects of macrophages on CVDs
| Diseases |
Effects |
Mechanisms |
References |
| Myocardial infarction |
Inflammatory reaction occurs at the injured site |
The number of cardiac macrophages increases |
[26]
|
| Cardiac hypertrophy |
Ejection fraction decline, area of cardiac hypertrophy increases |
The expression of Lgals3, CD68, FAS and TNNT2 greatly increased; miR-155/FOXO3a/caspase-1, IL-1 β, IL-18 pathway activation |
[27,28]
|
| Atherosclerosis |
Lipid deposition, monocyte macrophage infiltration, and plaque formation |
Foam cell formation, the phenotype of macrophage changes |
[29,30]
|
| Hypertension |
Reduce blood pressure |
“Hunt” for ET-1, which help blood vessels to remain relaxed |
[31]
|
CVDs: Cardiovascular diseases; ET-1: Endothelin-1; FAS: Tumor necrosis factor receptor superfamily, member 6; FOXO3a: Forkhead box O3a; IL: Interleukin; Lgals3: Lectin, galactoside binding, soluble 3; miR-155: MicroRNA-155; TNNT2: Troponin T type 2.
Macrophages and cardiac hypertrophy
Pressure overload-induced cardiac hypertrophy is one of the causes of HF[34]. Ren et al.[27] showed that cardiac hypertrophy induced by transverse aortic constriction (TAC) is associated with the activation of pro-inflammatory macrophages, characterized by the expression of CD68 and Lgals3 (lectin, galactoside binding, soluble 3). The expression of these markers increased progressively, accompanied by increased expression of TNF receptor superfamily, member 6 (FAS) and troponin T type 2 (TNNT2) and a reduction of ejection fraction (EF) during a 5-week period. They further showed that intervention with the drug dapagliflozin at the mid-term (2–5 weeks post-TAC) but not at the early stage inhibits the transition of macrophages to pro-inflammatory phenotype and improves cardiac function at later stages (5–8 weeks post-TAC). These findings suggest that the timing of intervention is critical for a successful outcome which may be dependent on the macrophage phenotype.
Macrophage-derived microRNA-155 (miR-155) promotes the development of cardiac hypertrophy in a paracrine fashion. Wang et al.[28] showed that infiltrated macrophages in uremic cardiomyopathy induce cardiomyocyte pyroptosis and hypertrophy, by secreting exosomes enriched with miR-155 that downregulate forkhead box O3a (FOXO3a) gene expression. Conversely, specific knockdown of miR-155 can reduce cardiac hypertrophy by restoring FOXO3a expression, thereby inhibiting the expression of pyroptosis markers caspase-1, IL-1 β, IL-18, and Gasdermin D (GSDMD). The studies suggest that macrophage-derived exosomes and the carried ncRNAs are involved in cardiac hypertrophy, and intervention at the early age of onset may improve the prognosis.
Macrophages and atherosclerosis
Atherosclerosis (AS) is a chronic inflammatory disease of large and medium-sized arteries characterized by plaque formation resulting from lipid accumulation and macrophage infiltration[35]. Macrophages are the most important cellular component in AS. These macrophages come from circulating monocytes that bind to endothelial cells and migrate to the subintima of the arterial wall and differentiate into macrophages. After uptaking lipids and their metabolites, the macrophages become foam cells[29], which cause the formation of fibrous plaques and lesions[36]. Sustained hydrolysis and re-esterification of cholesterol can result in the premature death of foam cells.
Macrophage phenotype is modulated by the AS microenvironment. At the early stages of plaque, M2 macrophage is the dominant phenotype that maintains plaque stability. As the disease progresses, the pro-inflammatory M1 macrophages become the dominant phenotype that causes plaque instability and rupture[30]. In early AS plaques, the apoptotic macrophages are efficiently cleared by surrounding macrophages, a process referred to as efferocytosis[37]. As the disease progresses, macrophage efferocytosis become defective, leading to the formation of an enlarged plaque necrotic core with decreased stabi lity and could potentially rupture to form a thrombus. In advanced plaques, macrophages die through pyroptosis and necroptosis. Pyroptosis is caused by the activation of inflammasomes[38,39]. Necroptosis causes plasma membrane rupture and release of DAMPs, which is a common feature in unstable human plaques. Macrophage autophagy enhances phagocytosis, which is inhibited in advanced plaques, leading to the accumulation of necrotic cells and plaque instability. Therefore, macrophages play an important role in all stages of atherosclerosis.
Macrophages and hypertension
Hypertension is a global health burden and a major risk factor for stroke, ischemic heart disease, and kidney disease[40]. It was shown that monocyte-derived macrophages might be the therapeutic target for the treatment of hypertension[31]. Macrophages can relax blood vessels by regulating the levels of endothelin-1 (ET-1)[31]. Mice fed a high salt food developed high blood pressure and reduced levels of macrophages[31,41]. This inverse relationship between blood pressure and levels of macrophages has also been documented in patients taking medications to treat immune system disorders[31]. The study suggests a relationship between macrophages and hypertension, and the macrophage polarization is critical for their interaction.
Macrophages and obesity
Obesity is a major risk factor for CVDs[42]. In 2003, Weisberg et al.[43] showed that macrophages are increased in adipose tissue in obesity and participate in inflammation. In recent years, several studies have confirmed that under normal conditions, adipose tissue macrophages are mainly M2 macrophages, contributing to an anti-inflammatory and reparative environment. Under the circumstances such as a high-fat diet, macrophages switch into M1 macrophages, which in turn trigger inflammation and promote obesity[44]. Several studies showed that Fgr kinase expression is higher in proinflammatory macrophages and correlates with obesity in mice and humans[45]. In addition, Brestoff et al.[46] showed that adipocytes and macrophages use intercellular mitochondrial transfer as an immunometabolic crosstalk mechanism in regulating metabolic homeostasis, but this process is impaired in obese humans. Taken together, the occurrence and development of obesity are closely related to the pro-inflammatory macrophages.
OVERVIEW OF THE INFLAMMASOME
The development of CVDs is associated with inflammation, and inflammasomes play an important role in mediating the inflammatory process and the pathophysiology of CVDs (Figure 2).
Figure 2.: Structure and activation of inflammasomes. A, The structures of inflammasomes NLRP3, NLRP1, AIM2, and NLRC4 are different; B, Once activated by different activators, inflammasomes are assembled. Subsequently, pro-caspase-1 is activated and induces the maturation and secretion of the downstream pro-inflammatory factor IL-1 β, IL-18. Caspase-1 cleaves GSDMD, which causes pyroptosis.AIM2: Absent in melanoma 2 factor; ASC: Apoptosis-associated speck-like protein containing a CARD; CARD: Caspase-recruitment domain; DAMPs: Damage-associated molecular patterns; FIIND: Function-to-find domain; GSDMD: Gasdermin D; HIN: Hematopoietic interferon-inducible nuclear antigens; IL: Interleukin; LRRs: Leucine-rich repeats; NACHT: Nucleotide-binding oligomerization domain; NLRC4: Nucleotide-binding oligomerization domain, leucine-rich repeat and caspase recruitment domain-containing 4; NLRP1: NOD-like receptor thermal protein domain associated protein 1; NLRP3: Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain- containing 3; P2X7: Purinergic ligand-gated ion channel 7; PAMPs: Pathogen- associated molecular patterns; PYD: Pyrin domain; T3S: Type III secretion system.
Structure and classification of inflammasomes
Inflammasomes are parts of the innate immune system that are activated in the presence of exogenous or endogenous danger signals. Inflammasomes have three components: intracytoplasmic PRRs, adaptor proteins apoptosis-associated speck-like protein containing caspase-recruitment domain (ASC), and effector proteins (pro-caspase-1). PRRs are the receptors that can sense signals from PAMPs or DAMPs[39,47]. ASC is an adaptor protein linking PRRs and pro-caspase-1 to form a complex called ASC-speck. Pro-caspase-1 can be cleaved and activated, triggering an inflammatory cascade. There are four classes of inflammasomes, namely nucleotide-binding and oligomerization domain (NOD)–like receptor thermal protein domain associated protein 1(NLRP1, or NALP1 [old name]), NOD-like receptor thermal protein domain associated protein 3 (NLRP3, or NALP3 [old name]), Nucleotide-binding oligomerization domain, leucine-rich repeat and caspase recruitment domain-containing 4 (NLRC4, or IL-1β converting enzyme protease activating factor [IPAF]), and absent in melanoma 2 factor (AIM2). Based on the receptor proteins, they can be classified into NOD-like receptor (NLR) family (NLRP1, NLRP3, and NLRC4) and non-NLR family (AIM2) inflammasomes[48]. AIM2 belongs to the interferon-inducible p200-protein (HIN200) family[49].
The NLRP3 inflammasome is a protein complex formed by NLRP3 protein, ASC, and pro-caspase-1. The NLRP3 receptor protein contains a pyrin domain (PYD) at the amino terminus, a nucleotide-binding oligomerization domain (NACHT) in the middle, and leucine-rich repeats (LRRs) at the carboxyl terminus. ASC bridges NLRP3 to pro-caspase-1 through its PYD-caspase-recruitment domain (CARD)[50]. Pro-caspase-1 is cleaved into two small subunits P20 and P10, which forms heterodimers to become active caspase-1[51]. Caspase-1 also contains a CARD that interacts with the CARD domain on ASC. The NLRP1 inflammasome consists of the NLRP1 protein, ASC, and pro-caspase-1. Only one NLRP1 in humans, but three paralogues exist in mice (NLRP1a, b, and c)[52]. NLRP1 contains a PYD domain at the N-terminus, followed by NACHT, LRRs, function-to-find domain (FIIND), and CARD. FIIND is a unique domain only found in NLRP1 that promotes the attachment of CARD to ASC[53]. AIM2 inflammasome was discovered by Fernandes-Alnemri et al.[54] in 2009 when searching for an inflammasome that could sense cytosolic DNA. The AIM2 inflammasome comprises the AIM2 receptor protein, ASC, and pro-caspase-1. AIM2 receptor protein consists of a PYD domain in N-terminal and 1 or 2 HIN domains in C-terminal[55]. The PYD domain of AIM2 binds to ASC through PYD-PYD interactions, while the HIN domain binds to cytosolic DNA[56]. The NLRC4 inflammasome is a protein complex composed of the NLRC4 receptor protein and pro-caspase-1. The NLRC4 receptor protein consists of a CARD domain (caspase recruitment domain) at the N-terminus, a NACHT domain in the middle, and LRRs domains at the C-terminus. Unlike NLRP3 and AIM2 receptor proteins that rely on ASC to recruit pro-caspase-1, NLRC4 recruits pro-caspase-1 through CARD-CARD interaction[57]. Thus, different inflammasome complexes have distinct features, which are tightly linked to activation pathways and function.
Activation of inflammasomes
Toll-like receptors (TLRs) activate TLR4/MyD88, TIR domain-containing adapter-inducing interferon-β (TRIF)/nuclear factor κB (NF-κB) signaling pathway, which induces the expression of NLRP3 receptor protein and the assembly of NLRP3 inflammasome[58]. When PAMPs or DAMPs are present, the PYD of the NLRP3 binds to the PYD in ASC, which then binds to pro-caspase-1 through CARD–CARD interactions. Subsequently, caspase-1 activates IL-1 β and IL-18. Caspase-1 also cleaves the gasdermin D protein (GSDMD) into the GSDMD N-terminal (GSDMD-NT) domain (p30) and the GSDMD C-terminal domain (p20)[59]. GSDMD-NT binds to phosphatidylinositol on the cell membrane to form a pore, leading to the release of cellular contents. This caspase-1-dependent cleavage of GSDMD is defined as canonical pyroptosis[60]. In the heart, NLRP3 inflammasome can be activated by lysosomal rupture and cathepsin B (CSTB) release[61], ion flow[62], endoplasmic reticulum stress[63], and reactive oxygen species (ROS)[64–68]. These signaling pathways collectively promote the development of CVDs.
Purinergic ligand-gated ion channel 7(P2X7) and panconnexin-1 are involved in NLRP1 activation. When stimulated by microbial and danger signals, adenosine triphosphate (ATP) accumulates in the extracellular matrix, leading to K+ efflux and opening of the panconnexin-1 channel, which releases more ATP[69]. High concentrations of ATP activate P2X7. Upon receiving the signal, the FIIND domain in NLRP1 receptor protein hydrolyzes to form two noncovalently associated polypeptides, leading to the activation of caspase-1[70]. Upon pathogen invasion and cell damage, cytosolic double-stranded DNA is released from the nucleus or mitochondria[71]. AIM2 inflammasome is able to sense cytosolic DNA and further activates caspase-1, resulting in an inflammatory response[72]. NLRC4 is mainly activated by bacterial flagellin and components of the bacterial type III secretion system (T3SS). T3SS is a transmembrane molecular needle-like structure that is found in some Gram-negative bacteria[73,74]. These bacterial proteins activate the NLRC4 inflammasome through the interaction with the inhibitor of apoptosis protein (NAIP) in the NLR family. NAIP2 bind to needle proteins, whereas NAIP5 binds to flagellin[75]. In humans, T3SS proteins activate NLRC4 inflammasome by interacting with human NAIP (hNAIP)[76]. Taken together, different inflammasomes are activated by different mechanisms.
INFLAMMASOMES IN CARDIOVASCULAR DISEASES
Inflammation plays an important role in the development of CVDs. The most current research focused on the NLRP3 inflammasome[77,78], and other inflammasomes were poorly studied[79] (Table 2).
Table 2. -
Effects of inflammasomes on
cardiovascular diseases
| Diseases |
Effects |
Mechanisms |
References |
| Myocardial infarction |
Cardiac inflammation, fibrosis, remodeling |
CaSR or Dectin-1 increases, TAX1BP1 decreases, NLRP3/AIM2/NLRC4 activation |
[80–83]
|
| Cardiomyopathy |
Transient or sustained local inflammatory response |
CVB3 induced viral myocarditis: NLRP3, IL-1β, Caspase-1, ASC increase. Diabetic cardiomyopathy: overproduction of ROS and P2X7R activation; lncRNA Kcnq1ot1 or miR-30d activates NLRP3 |
[84–87]
|
| Atherosclerosis |
Vascular inflammation, endothelial damage, lipid and cholesterol accumulation, and thrombosis occur |
HMGB1 promote foam cell formation; oxLDL activate NLRP3 to mediate the early inflammation; NLRP1, NLRC4, AIM2 activation |
[88–91]
|
| Hypertension |
Inflammation, vascular endothelial function damage |
NLRP3 activation, caspase-1, IL-1β increase |
[92–94]
|
| Heart failure |
Myocardial fibrosis, ventricular remodeling |
NLRP3 activation; IL-1β increases; NLRC4, AIM2 activation |
[79,95,96]
|
AIM2: Absent in melanoma 2 factor; ASC: Apoptosis-associated speck-like protein containing a caspase-recruitment domain; CaSR: Calcium sensing-receptor; CVB3: Coxsackievirus B3; HMGB1: High mobility box-1 protein; IL: Interleukin; lncRNA: Long non-coding RNA; miR-30d: microRNA-30d; NLRC4: Nucleotide-binding oligomerization domain, leucine-rich repeat and caspase recruitment domain-containing 4; NLRP1: NOD-like receptor thermal protein domain associated protein 1; NLRP3: Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3; oxLDL: Oxidized low-density lipoprotein; P2X7R: Purinergic ligand-gated ion channel 7 receptor; ROS: Reactive oxygen species; TAX1BP1: Tax1 binding protein 1.
Inflammasome and myocardial infarction
Studies have shown that cardiac fibroblasts sense DAMPs and activate inflammasomes in response to MI[97]. Infiltration of neutrophils is an important feature of MI. Ren et al.[80] showed that the calcium sensing-receptor (CaSR) on neutrophils promotes ventricular remodeling after infarction by activating the NLRP3 inflammasome. Li et al.[81] showed that Dectin-1, a c-type lectin, is involved in NLRP3 inflammasome activation after MI in an NF-κB–dependent manner. They further showed that the upregulation of Dectin-1 contributes to cardiac remodeling. Therefore, Dectin-1 inhibition represents a potential therapeutic approach for treating ischemic diseases.
Using a rat model of MI, Xiao et al.[98] showed that administration of β-Asarone, which is a component of Acorus tatarinowii Rhizoma, was able to reduce infarct size by inhibiting NLRP3 inflammasome signaling pathway. Xu et al.[82] showed that the levels of Tax1 binding protein 1 (TAX1BP1) were decreased in the heart tissues of patients with ischemic heart disease. They further showed that overexpression of TAX1BP1 in the myocardium reduced infarct size, inhibited inflammasome activation, and improved cardiac function. Yang et al.[99] demonstrated that Hyperoside could reverse left ventricular (LV) remodeling after MI by upregulating autophagic flux and inhibiting the NLRP1 inflammasome pathway. The regulatory role of autophagy in inflammasome activation was confirmed by another study showing that mitophagy is impaired in peri-infarct regions of LV in mice with type 2 diabetes. The defective mitophagy causes the release of mitochondrial DNA, leading to the activation of AIM2 and NLRC4 inflammasomes in cardiac macrophages and cardiomyocytes[83]. Thus, inflammasomes may serve as novel therapeutic targets in preventing MI.
Inflammasome and cardiomyopathy
Cardiomyopathy is a condition caused by myocardial injury. Studies have shown that NLRP3 is implicated in developing both ischemic and non-ischemic cardiomyopathy in mice[100,101]. Viral myocarditis is a frequent cause of dilated cardiomyopathy. Coxsackievirus B3 (CVB3)-induced myocarditis is characterized by increased ROS and K+ efflux, which activates the NLRP3 inflammasome[84]. The association between increased glucose levels and the activation of NLRP3 inflammasome has been documented in animal studies[102]. Zhang et al.[85] showed that high glucose-induced activation of NLRP3 inflammasome was mediated by the overproduction of ROS and P2X7 receptor (P2X7R), which can be attenuated by relaxin. Yang et al.[86] showed that the non-coding RNA lncRNA Kcnq1ot1 expression is elevated in the left ventricular tissue of diabetic mice. Silencing Kcnq1ot1 alleviates diabetic cardiomyopathy by inhibiting pyroptosis. In addition, miR-30d was also reported to mediate NLRP3 activation and pyroptosis[87]. Although the factors triggering cardiomyopathy are different, they all contribute to the development of the disease by activating inflammasomes. Therefore, targeting relevant molecules of inflammasome pathways holds promise for treating cardiomyopathy.
Inflammasomes and atherosclerosis
Vascular changes associated with atherosclerosis include inflammation, endothelial dysfunction, lipid, and cholesterol deposition. In this process, inflammasomes are involved in cholesterol crystallization and endothelial cell damage by activating caspase-1, IL-18, and IL-1β[103]. Wang et al.[88] showed that activation of NLRP3 inflammasome could promote foam cell formation by inducing the secretion of high mobility box-1 protein (HMGB1) in human vascular smooth muscle cells (VSMCs).
Inflammasomes can be activated by cholesterol crystals and oxidized low-density lipoprotein (oxLDL)[104]. Using, Duewell et al.[89] showed that NLRP3 could be activated in human peripheral blood monocytes and mouse macrophages by cholesterol crystals. In macrophages, oxLDL-induced NLRP3 inflammasome activation is mediated by ROS[105]. Apolipoprotein E (Apo E) is important for the physiological metabolism of cholesterol. Apo E knockout mice spontaneously develop AS lesions. It was shown that the expression of both IL-18 and IL-18 receptors are increased in the vicinity of atherosclerotic plaques developed in the Apo E knockout mice[106]. Increased levels of IL-18 are associated with vascular inflammation and plaque instability. A clinical study showed a systemic alteration of NLRP1 and NLRV4 in AS patients compared with healthy controls[107]. Another study reported that the increased levels of plasma triglyceride and VLDL were associated with the activation of NF-κB, which in turn triggers the activation of the NLRP1 inflammasome in human arterial endothelial cells (HAECs)[90]. It was shown that the expression of AIM2 is increased around the necrotic core of atherosclerotic lesions[108]. The necrotic cells release dsDNA, which activates the AIM2 inflammasome and the subsequent release of inflammatory cytokines[91]. Taken together, atherosclerotic plaque components activate inflammasomes, which release inflammatory factors to promote the development of atherosclerosis.
Inflammasomes and hypertension
An initiating step in hypertension is chronic inflammation that involves macrophage infiltration and vascular endothelial dysfunction[109]. Clinical studies detected high levels of IL-1β in the peripheral blood of hypertension patients. Avolio et al.[92] showed increased mRNA levels of caspase-1, NLRP3, and IL-1β in the amygdala, hypothalamus, and brainstem from the spontaneously hypertensive rats (SHR). The expression levels of NLRP3 inflammasome and its downstream pro-inflammatory cytokines can be used to predict the severity of hypertension[110].
Blood pressure is regulated by neuro- and humoral factors, which are affected by the NLRP3 inflammasome. Qi et al.[93] showed that high-salt–induced hypertension is associated with NF-κB activation and increased NLRP3, IL-1β, and oxidative stress in the hypothalamic paraventricular nucleus (PVN). Inhibition of NF-κB in the PVN suppresses NLRP3 and attenuates hypertension[93]. The phenotypic transformation of VSMCs from a contractile phenotype to a synthetic phenotype contributes to vascular remodeling and hypertension. Ren et al.[94] showed that Ang II-induced phenotypic transformation and hypertension were attenuated in NLRP3-deficient mice, suggesting that Ang II-induced hypertension is mediated by the NLRP3 inflammasome. In addition, the NLRP3 inflammasome is also a predictive marker in the early stage of hypertensive diseases[111]. Krishnan et al.[112] showed that N-(([1,2,3,5,6,7-Hexahydro-s-indacen-4-yl]amino)carbonyl)-4-(1-hydroxy-1-methylethyl)-2-furansulfonamide monosodium salt (MCC950), a specific inhibitor of NLRP3, was effective in reducing blood pressure and renal inflammation in mice with established hypertension. These studies lay the foundation for treating hypertension by inhibiting the activation of the inflammasome. In summary, inflammasomes play important roles in both the pathogenesis of hypertension and vascular remodeling, and relevant factors can be used for the prediction of hypertension. Thus, targeting inflammasomes is a therapeutic approach to treat hypertension.
Inflammasomes and heart failure
HF is caused by multiple factors, including neurohormone changes and stress that contribute to ventricular remodeling and fibrosis. It was shown that activation of the NLRP3 inflammasome and the release of IL-1β and IL-18 promote cardiac fibrosis and chronic HF[113]. Bracey et al.[95] showed that the transgenic mice overexpressing calcineurin transgene (CNTg) develop cardiac hypertrophy, inflammation, apoptosis and ventricular dilatation, which can be reduced by deleting Nlrp3.
Calcium/calmodulin-dependent protein kinase II δ (CaMK II δ) is responsible for the progression from hypertrophy to HF resulting from pressure overload. One study showed that pressure load-induced expression of IL-1β and IL-18 was attenuated by CaMK II δ deletion in cardiomyocytes[96]. It is reported that ten-eleven-translocation-2(TET2) mutation is associated with an increased risk of developing HF. TET2 deficiency results in increased IL-1β expression, which can be blocked by NLRP3 inhibitor MCC950[113]. A clinical study showed that the expression AIM2 and NLRC4 inflammasomes were increased in HF, while the expression of NLRP3 and NLRP1 did not change. Probenecid was able to alleviate chronic HF by reducing the activation of AIM2 and NLRC4 inflammasomes[79]. Thus, inflammasomes are involved in the development of HF and targeting NLRP3 or IL-1 β will inhibit the development of the disease.
THERAPEUTIC STRATEGIES TARGETING INFLAMMASOMES FOR THE TREATMENT OF CARDIOVASCULAR DISEASES
Macrophage polarization is implicated in the development of CVDs. Zhang et al.[114] showed that ginsenoside Rb1 enhances the stability of atherosclerotic plaques by promoting anti-inflammatory M2 macrophage polarization and reducing matrix metalloproteinase-9 (MMP-9) expression. Kim[115] showed that macrophage M2 polari zation is mediated by MAF bZIP transcription factor B (MafB), which helps to remove cholesterol from the foam cells.
For the treatment of CVDs, strategies targeting the activation of inflammasomes and their downstream signaling pathways are being explored[116]. Abbate et al.[117] evaluated the effects of a genetically engineered mouse IL-1β neutralizing antibody in a mouse model of acute MI and showed that the antibody could attenuate cardiac enlargement and myocardial dysfunction. A phase IIb clinical trial tested the effect of canakinumab (an antibody that neutralizes IL-1β), and the result showed that canakinumab could reduce inflammation without affecting low-density lipoprotein cholesterol or high-density lipoprotein cholesterol[118]. Kawaguchi et al.[119] showed that inflammasome activation in cardiac fibroblasts is involved in the initial inflammatory response triggered by ischemia-reperfusion (I/R) injury in the heart. They showed that infarct development and cardiac fibrosis was diminished in ASC or caspase-1 knockout mice. Gage et al.[120] showed that caspase-1 deletion significantly reduced the atherosclerosis rate of ascending aorta in apolipoprotein E (Apoe) (−/−)mice. Using a mouse acute myocardial infarction (AMI) model, Mezzaroma et al.[121] demonstrated the presence of ASC, cryopyrin, and caspase-1 in the granulation tissue and cardiomyocytes bordering the infarct. They further showed that siRNA or drugs targeting NLRP3 and P2X7 receptors could inhibit the activation of inflammasomes and reduces infarct size. Omega-3 fatty acids (ω-3 FAs) have been shown to inhibit the activation of NLRP3 inflammasomes through G protein-coupled receptor 40(GPR 40) and GPR120 signaling pathways[122]. MCC950 is a specific small molecule inhibitor, which can selectively block the activation of NLRP3 inflammasomes[123], but the mechanism of the inhibitory effect of MCC950 on NLRP3 was fully understood. Wang et al.[124] showed that MCC950 restores fatty acid uptake and utilization by inhibiting AKT activation and increasing the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) in obese mice with HF.
THE SITE AND NATURE OF THE BIOLOGICAL EVENT OF MACROPHAGE AND INFLAMMASOME
Macrophages and inflammasomes play distinct roles at different levels in inflammation through crosstalk (Figure 3). The inflammasome system exists within macrophages. Schmacke et al.[125] found that human induced pluripotent stem cells could differentiate into macrophages in vitro, and different toxins can be used to activate the NLRP3 inflammasome in macrophages to release IL-1 β and IL-18[125]. Moreover, it has been shown that CD1d1 intrinsic signaling of macrophages controls the expression of NLRP3 inflammasome in response to inflammation[126]. AIM2 inflammasome is also predominantly expressed in monocytes/macrophages in HF[79].
Figure 3.: The correlation between macrophages and inflammasomes. The inflammasome system is present in macrophages. The activation of inflammasomes in macrophages can cause macrophage pyroptosis. The released inflammatory factors can induce macrophage polarization and further exacerbate the activation of the inflammasome.DAMPs: Damage-associated molecular patterns; GSDMD: Gasdermin D; IL: Interleukin; PAMPs: Pathogen- associated molecular patterns; TNF-α: Tumor necrosis factor-α.
Inflammasome activation may trigger macrophage pyroptosis. It has been shown that janus kinase 2 V617F (JAK2VF) mutant clonal hematopoiesis causes changes in cellular metabolism, which lead to DNA oxidative damage, resulting in activation of AIM2 inflammasome and production of IL-1 β, leading to pyroptosis[127]. The consequence of these events is an increased macrophage burden and the formation of atherosclerotic lesions. Several other reports have shown that nicotine acts to induce macrophage pyroptosis in atherosclerosis through histone deacetylase 6(HDAC6)/NF-κB/NLRP3 signaling pathway[128]. Triggering receptor expressed on myeloid cells 2 (TREM2)/β-catenin can attenuate NLRP3 inflammasome-mediated macrophage pyroptosis and promote bacterial clearance of pyogenic bacteria[129].
Cytokines (TNF-α, IL-6) secreted by macrophages are widely implicated in the pathogenesis of CVDs by mediating cardiomyocyte-fibroblast crosstalk, promoting cardiac hypertrophy and fibrosis, inhibiting cardiomyocyte contractile function, stimulating microvascular inflammation and dysfunction. Importantly, these cytokines induce the activation of macrophages and are presumably associated with inflammasome activation[130–132]. In addition, inflammasomes secrete IL-1β and IL-18 that further activate macrophages in the heart and cause the interconversion of M1 and M2 macrophages. Multiple studies have shown that the NLRP3 inflammasome mediates M1 macrophage polarization[133]. M1 macrophage polarization is also suppressed when the NLRP3 inflammasome is inhibited, along with promoting M2 macrophage polarization[134]. In addition, the NLRC4 inflammasome is highly implicated in M2 macrophage polarization, and knockout of NLRC4 reduces M2 macrophages in a mouse model of non-alcoholic fatty liver disease (NAFLD)[135]. Thus, the site and nature of the biological event of macrophage and inflammasome are critical for the development of diseases.
CONCLUSION
Macrophages and inflammasomes are involved in developing CVDs, including MI, hypertension, cardiomyopathy, atherosclerosis, and HF. A better understanding of the mechanisms underlying the activation and regulation of inflammasomes and macrophage polarization will provide new targets for the prevention, diagnosis, and treatment of the diseases. Strategies targeting NLRP3 inflammasome have shown promising results. The development of specific inhibitors against other inflammasomes is currently being investigated.
FUNDING
This work was supported by the National Natural Science Foundation of China (81870194 and 91849122 to Y. Li, and U1601227 to XY), China Postdoctoral Science Foundation (No. 2021M702394 to YW), Jiangsu Province of Excellent Postdoctoral Program (to YW), Jiangsu Province Peak of Talent in Six Industries (BU24600117 to Y. Li), National Natural Science Foundation of China (92168203 and 82241201) and Jiangsu Cardiovascular Medicine Innovation Center (No. CXZX202210).
AUTHOR CONTRIBUTIONS
YZ, JT, and YL collected references, wrote parts of the paper, and drew figures. YW, LL, CW, and XY collected references and drew tables. YL conceived, wrote, and revised the paper.
CONFLICTS OF INTEREST STATEMENT
The authors declare that they have no conflict of interest with regard to the content of this manuscript.
DATA SHARING STATEMENT
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
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