Innate immune cells of the myeloid lineage form a kidney surveillance system that is poised to quickly react to a variety of insults, from pathogens to endogenous threats. Circulating and resident myeloid cells interact with the various kidney substructures, and deficits in this interaction are the root cause of many kidney disorders. Recent efforts in single-cell sequencing have provided clarity on many intricacies of the kidney-myeloid interface (1–4). This review will provide an overview of current knowledge regarding the interactions between myeloid cells and native kidneys and provide an updated framework for future studies investigating alterations in this interface.
Myeloid Cells in Normal Kidney Function
Myeloid cells are important to kidney health and include monocytes, macrophages, dendritic cells, and neutrophils. Neutrophils are circulating myeloid cells that are rapidly mobilized to sites of inflammation and infection. Recruited neutrophils eliminate pathogens via phagocytosis and via release of intracellular contents, including antimicrobial peptides (degranulation) and neutrophil extracellular traps (NETs), which physically trap bacteria—much like a spider’s web traps prey (Figure 1A). Neutrophils are abundant yet short lived: their survival, both in circulation and after recruitment to tissues, is typically limited to <5 days (5).
Macrophages are comparatively much longer lived (on the order of months) and have the broadest roles in organ homeostasis, from neutralizing threats to orchestrating adaptive repair after tissue injury (Figure 1B). Although historically dichotomized into polar M1 (proinflammatory) and M2 (anti-inflammatory) states, macrophages are now recognized to exist as several subsets along a spectrum of activity (6,7). Macrophages engulf and destroy perceived threats, such as foreign material and senescent or abnormal endogenous cells. Dendritic cells similarly recognize these foreign antigens but chiefly serve to present these to T cells, thereby activating the adaptive immune system (Figure 1C) (8). Kidney macrophages largely derive from infiltrating bone marrow–derived monocytes, but there also exists a subset of embryonically derived and self-renewing resident macrophages (2). Resident macrophages and dendritic cells—collectively referred to as histiocytes—are concentrated in the medulla because the hypersaline medullary milieu favors their recruitment and enhances their defense capacity (9). This spatial zonation is thought to enable more rapid response to pathogen- and damage-associated molecular patterns. Whereas pathogen-associated molecular patterns are bacterial and viral epitopes, damage-associated molecular patterns are endogenous signals of noninfectious damage released by structural cells of the kidney, including epithelial cells, endothelial cells, and fibroblasts (2,10). For example, in acute tubular necrosis, leached uromodulin acts as a damage-associated molecular pattern to attract macrophages and dendritic cells to the site of tubular damage (11). Similarly, in response to retrograde colonization by uropathogens, epithelial cells of the kidney pelvis release chemokines to recruit neighboring phagocytes (2). These and many more coordinated immune responses to threat are a product of intricate kidney-myeloid crosstalk.
Myeloid cells communicate alerts bidirectionally with neighboring cells by way of cytokines. Important cytokines in kidney homeostasis are outlined in Table 1. Of these, IL-6 signaling has important, complex, and, at times, conflicting roles in controlling inflammation (12). IL-6 is proinflammatory in the acute response to tissue injury, setting off a cascade of immune responses, including B- and CD4+ T-cell activation, and the production of acute-phase proteins, such as C-reactive protein and fibrinogen by hepatocytes (13). Tight regulation of IL-6 signaling in the kidney microenvironment is important for mounting an appropriate inflammatory response (14). In early tubular injury, proinflammatory macrophages secrete large amounts of IL-6 to stimulate the activation of neighboring fibroblasts, epithelial cells, and progenitor cells (15). In adaptive kidney repair, this controlled burst of acute inflammation is followed by a period of wound healing and resolution of injury (16), which is coordinated by distinct subsets of macrophages (1). Profibrotic macrophages contribute to the activation of myofibroblasts at the site of injury (17), which produce the collagenous extracellular matrix that is used to provide structural support to the cellular remodeling that occurs after tissue injury (4,7). Activation of the fibrotic phase is typically effected by IL-4, IL-13, TGF-β (17), and—paradoxically—also IL-6 (18). In summary, IL-6 stimulates production of critical proteins and recruits myeloid cells involved in induction and resolution of the inflammatory response.
Table 1. -
Cytokines in kidney homeostasis
||Pleiotropic cytokine with local and systemic roles in the inflammatory response
||Proinflammatory cytokines released upon activation of the NLRP3 inflammasome, a multimeric protein complex that can sense a variety of substrates, such as monosodium urate, glucose, ATP, and multiple bacterial antigens (17). This pleiotropy is possible because NLRP3 does not directly recognize these as discrete ligands but instead detects specific changes to cellular homeostasis resulting from their presence (18). Once activated, NLRP3 inflammasome components perform activating cleavage of precursor forms of IL-1β and IL-18, which are then released locally during programmed inflammatory cell death (pyroptosis) (17)
| IFN family cytokines
||Released upon detection of viral pathogen-associated molecular patterns (critical role in host defense)
||Promotes neutrophil migration to sites of kidney injury and potentiates phagocytosis
| CCL2 (MCP-1)
||Recruit monocytes to the glomerular endothelium and guide the infiltration of monocytes-turned-macrophages to the kidney parenchyma during injury
| CCL3 (MIP-1)
| CX3CL1 (fractalkine)
||Facilitate neutrophil infiltration of the kidney after injury
| CXCL8 (IL-8)
||Promote alternative (M2-type) activation of macrophages
aSee text for further details.
Mechanisms of Myeloid Cell Dysfunction in Kidney Pathology
Myeloid cells are involved in virtually all forms of kidney dysfunction and overt kidney disease. Their contributions to pathology can be broadly divided into whether the myeloid cells become trapped in a dysfunctional inflammatory loop in response to injury, or whether the myeloid cells are themselves the primary cause of injury due to an intrinsic defect (Figure 2).
Myeloid Cells in Chronic Kidney Inflammation and Fibrosis
Proinflammatory macrophages can perpetuate inflammation, especially when there is continued presence of damage-associated molecular patterns (Figure 2A) (7). In diabetic kidney disease (DKD), sustained hyperglycemia is associated with pervasive cytokine signaling and macrophage infiltration (19,20). In early DKD, immune cells have been shown to infiltrate the kidney at a density seven to eight times that in those without diabetes (21). Whereas activated macrophages are mostly restricted to the glomerulus in early DKD, there is subsequent progressive infiltration of the neighboring parenchyma as chronic inflammation develops (22). This persistent inflammation can lead to progressive fibrosis, the common end point in many CKDs (23).
An overwhelming acute inflammatory signal can also prompt chronic inflammation and kidney scarring. Drug-induced acute interstitial nephritis (AIN) is a local hypersensitivity reaction that represents the third most common cause of AKI in patients admitted to the hospital (24). Surveillant dendritic cells recognize the offending drug, and subsequent T-cell activation then sets off an inflammatory cascade that can recruit a broad spectrum of myeloid cells, including monocytes in transit, neutrophils, and often also eosinophils (24). The magnitude of this inflammatory cascade and the consequent degree of kidney impairment are highly variable and difficult to predict in drug-induced AIN (25,26). At one extreme, an intense inflammatory response and marked interstitial influx of various myeloid cells can promote severe AKI with pyuria and leave dysregulated residual inflammation, marked fibrosis, and chronic kidney impairment in its wake. Kidney biopsy can enable assessment of the degree of acuity, nature of myeloid cellular infiltrate, and an assessment of fibrosis and chronicity (27).
Myeloid Cells Recruited to Pathogenic Glomerular Immune Complexes
Immune complexes can form or deposit within the glomerulus as a result of autoantibody formation—a failure of the adaptive immune system. Innate immune cells of the myeloid lineage are programmed to detect and eliminate abnormal autoantigens. This type of immune response is protective against malignancy, for example, but destructive when otherwise healthy tissues are targeted, such as in GN (Figure 2B). IgA nephropathy results from deposition of immune complexes within the glomerular mesangium. Nephritogenic galactose-deficient IgA1 is the product of underglycosylation of the IgA hinge region, a process that is augmented by IL-6 signaling (28,29). Galactose-deficient IgA1 is the target antigen of autoantibody formation in IgA nephropathy, and deposition of these immune complexes in the mesangium leads to proliferative changes, including endocapillary and mesangial hypercellularity with local cytokine release, complement system activation, and macrophage infiltration (30). In IgA nephropathy, mesangial macrophage recruitment on kidney biopsy is associated with a more severe clinical course of disease (31). Within proliferative glomerular lesions in IgA nephropathy, the amount of CD163—a cell surface receptor for hemoglobin-haptoglobin complexes (32) that is specific to monocytes and monocyte-derived macrophages and that can be used as histopathologic proxy of their density—is inversely correlated with eGFR (33).
Pathologic macrophage and neutrophil responses to deposited immune complexes likewise contribute to kidney damage in anti–glomerular basement membrane disease and in lupus nephritis (27). In anti–glomerular basement membrane disease, experiments in mice have shown that an Fc receptor on the neutrophil cell surface directly binds the deposited immune complexes and promotes NET formation by the recruited neutrophil (34). Likewise, in lupus nephritis, antibodies complexed to nuclear autoantigens are deposited in the glomerulus, which activates the complement system and recruits various leukocytes (35). Macrophages exposed to autoantibody immune complexes in lupus nephritis adopt a distinct metabolic state that is skewed toward glycolysis—a phenotype that is similar, but not identical, to M1 macrophages (36). It has been proposed that targeting this unique macrophage metabolism may help treat lupus nephritis (36). In addition to their role in recognizing immune complex deposits, neutrophils have extrarenal roles in SLE and lupus nephritis. Neutrophils in SLE are primed to undergo NETosis, which externalizes immunogenic nuclear material and can promote SLE pathogenesis (37). In particular, low-density granulocytes—a subset of largely immature and proinflammatory neutrophils (38)—engage in more NET formation in SLE (39).
Cleaved Cell Surface Proteins in Kidney Injury
Maladaptive local release of myeloid intracellular content (cytokines, granules, NETs) can promote to kidney injury instead of promoting organ defense. Certain proteins cleaved from the cell surface of myeloid cells have been similarly identified as mediators of kidney injury. The urokinase-type plasminogen activator receptor (uPAR) is a membrane-bound protein found on many cells that is cleaved in the setting of inflammation (40,41). The soluble uPAR (suPAR) protein mediates pathologic activation of podocyte αvβ3-integrin signaling (40,42) and has been implicated in a broad range of kidney disease phenotypes, including all-cause CKD (43), APOL1-associated kidney disease (44), and autosomal dominant polycystic kidney disease (45). A variety of myeloid and nonmyeloid cells are known to shed suPAR (41,46), although bone marrow–derived immature myeloid lineage cells were identified as the primary source of high circulating suPAR levels in a mouse model (38). Other cleaved transmembrane proteins have been implicated in modulating inflammatory kidney damage by acting as decoy receptors that can scavenge cytokines and other inflammatory mediators. This includes soluble receptors for advanced glycemic end products in DKD (47,48) and soluble TNF receptor 1 (sTNFR-1) and sTNFR-2. Elevations in serum soluble receptors for advanced glycemic end products and sTNFRs have been associated with kidney dysfunction, all-cause mortality, and cardiovascular events (47,49,50). There is debate about whether this reflects heightened activity of the nonscavenged ligands, or instead whether the decoy receptors act as reservoirs that prolong the half-life of these inflammatory mediators (51). suPAR, sTNFR-1, sTNFR-2, and other proteins related to myeloid cell function have recently been shown to robustly correlate with histologic disease severity and clinical outcomes across a spectrum of kidney disease etiologies (52).
Kidney Sequelae of Intrinsic Myeloid Cell Defects
Thus far, this review has focused on immune cells amplifying incendiary damage in the kidney microenvironment by reacting to abnormal stimuli, such as pervasive inflammation or intruding immune complexes. Conversely, there exist scenarios where myeloid cells acquire defects outside of the kidney niche and are primary instigators of kidney disease (Figure 2). The next sections will explore how inherent myeloid cell defects, such as autoimmune activation or malignant transformation of these cells, can compromise kidney homeostasis.
Autoimmune Activation of Myeloid Cells in ANCA-Associated Vasculitis
Neutrophils, the most abundant myeloid cell in the circulation, participate in virtually all forms of autoimmune GN through varying mechanisms of injury (53). In ANCA-associated vasculitis, the contents of neutrophil granules are targeted by anti–proteinase 3 and/or anti-myeloperoxidase autoantibodies (Figure 2C). Upon autoantigen binding, neutrophils are activated: cytokines, proteases, and microparticles (54) are released via degranulation and NET formation, leading to endothelial injury and necrotizing damage of the glomerulus (55). The release of damaging neutrophil granule contents by NETosis is increasingly recognized as a common pathophysiologic mechanism in many systemic immune disorders affecting the kidney (53). The contents of these granules cooperatively disrupt glomerular endothelium integrity; activate complement; and induce the recruitment of monocytes, which are then primed to infiltrate glomeruli and amplify inflammatory and fibrotic insults therein. ANCA-stimulated neutrophils also release B cell–activating factor, which further perpetuates autoantibody formation and neutrophil autoactivation. Diverse macrophage populations amplify inflammatory insults in ANCA-associated vasculitis, and urinary biomarkers of their presence have been clinically translated into markers of disease activity. CD163 is cleaved from the macrophage and monocyte cell surface in the setting of inflammation (56), and urinary soluble CD163 is a reliable biomarker of active ANCA-associated vasculitis (57,58).
Kidney Sequelae of Malignant Myeloid Cell Disorders
Clonal and dysplastic cells of the myeloid lineage can manifest kidney sequelae as a direct consequence of disease and due to treatment-related toxicity (Figure 2D) (59,60). Acute myeloid leukemia can present with AKI due to tumor lysis syndrome or thrombotic microangiopathy (61). Less commonly, it can precipitate glomerular phenotypes, such as membranous nephropathy or FSGS (62), or cause direct injury through malignant parenchymal infiltration (63). Chronic myeloid leukemia has been associated with membranous nephropathy, minimal change disease, and membranoproliferative GN (60). Other myeloproliferative neoplasms—particularly primary myelofibrosis—have been associated with progressive kidney dysfunction and heavy proteinuria (62). Systemic autoimmune disorders are diagnosed in 10%–20% of individuals with myelodysplastic syndromes and, in a recent case series of individuals diagnosed with myelodysplastic syndrome who underwent kidney biopsy for AKI, more than half were diagnosed with rare glomerulopathies (64).
Clonal hematopoiesis of indeterminate potential (CHIP) is a newly recognized premalignant state that is associated with systemic inflammatory damage (65). With age, clonal populations of myeloid cells emerge as a result of mutations in bone marrow hematopoietic stem cells, commonly in epigenetic regulators such as TET2, DNMT3A, and ASXL1 (65,66). When the proportion of clonal cells in circulation reaches ≥4%, but there is no evidence of malignant transformation, severe cytopenias, or other World Health Organization–defined disorder, this is labeled CHIP (67). CHIP affects at least 15% of the general population aged ≥65 and it portends a 1.4-fold higher risk of all-cause mortality (65), an 11-fold higher risk of hematologic malignancy (65,66), and a two-fold higher risk of cardiovascular disease (68) that is independent of, and on par with, traditional cardiovascular risk factors (69). CHIP cells produce high levels of inflammatory cytokines (70,71), and dysregulated IL-6 signaling has been causally implicated in CHIP pathogenesis (72). Macrophages in mouse models of CHIP display an impaired ability to resolve inflammation (73) and contribute to kidney tubulointerstitial fibrosis (74,75). We recently showed that CHIP was associated with worse baseline kidney function, more kidney failure events, and higher rates of anemia in a small cohort of individuals with advanced CKD followed for up to 12 years. A cross-sectional analysis of 112 individuals with ANCA-associated vasculitis noted a higher prevalence of CHIP compared with age- and sex-matched healthy controls (30% versus 14%) (76). At present, there exist no evidence-based interventions for CHIP and, as such, no clinical guidelines pertaining to its surveillance or management (77). This is expected to change within the next few years because therapeutic strategies aimed at modifying clonal burden or controlling downstream inflammatory damage are in development (78). It is currently unknown whether these potential treatments may improve kidney or cardiovascular outcomes in patients with CHIP and kidney disease. First validating and exploring the causality and directionality of the association between CHIP and kidney disease is critical to ensure that patients affected by kidney disease are adequately considered in this ongoing effort.
Targeting Myeloid Cells in Kidney Disease
Given their broad involvement in inflammation and fibrosis, it is unsurprising that many therapies in kidney disease target myeloid cells. Among their numerous sites of action, glucocorticoids induce a type of kidney M2 macrophage polarization (78) and suppress IL-6 signaling in podocytes (79); for this reason, they are used to dampen inflammation across a broad spectrum of kidney disorders—from ANCA-associated vasculitis and lupus nephritis to nephrotic syndromes to severe cases of drug-induced AIN. Curiously, mineralocorticoids have the opposite effect: aldosterone induces a type of M1 activation of macrophages through direct actions on mineralocorticoid receptors within myeloid cell nuclei. Both hematopoietic-specific deletion of the mineralocorticoid receptor and inhibition with mineralocorticoid receptor antagonists were shown to be kidney protective in a mouse model of GN (80). The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) phase 3 randomized control trial showed that finerenone (a mineralocorticoid receptor antagonist with both anti-inflammatory and antifibrotic properties ) delayed the progression of DKD (82). Many other components of the renin-angiotensin-aldosterone system have intricate roles in controlling the kidney inflammatory versus fibrotic balance (83). The targeted inhibition of certain myeloid cell intracellular proteins is being investigated in immune-mediated GN . Spleen tyrosine kinase inhibitors are in early stages of clinical assessment as therapies for ANCA-associated vasculitis (84) and IgA nephropathy (85), and inhibitors of diverse pathologic NETosis effector proteins have been assessed in preclinical models of ANCA-associated vasculitis (86).
Some of the most prescribed treatments in kidney failure (hemodialysis and peritoneal dialysis) have broad effects on the inflammatory network. Multiple patient- and modality-related factors contribute to inflammation, including uremic toxins and foreign bodies such as dialysis catheters and arteriovenous fistula graft material (87). Chronic elevations in IL-6, IL-1β, and other inflammatory markers are common in patients on long-term dialysis and have been associated with higher mortality, cardiovascular events, anemia, malnutrition, mineral bone disease, and cognitive decline in this population (87). Although not yet used in routine practice, proinflammatory cytokine blockade may help mitigate some of these complications, with supporting evidence for canakinumab (an IL-1β blocker) in the secondary prevention of cardiovascular events, which showed particular efficacy in patients with CKD (88), and ziltivekimab (an IL-6 blocker) for patients on hemodialysis with inflammatory anemia and erythropoietin hyporesponsiveness (89).
Circulating and resident myeloid cells are critical determinants of kidney health and disease. Although their role is to defend the kidney after injury, an imbalance or hyperactivation in any part of their regulatory network can, conversely, perpetuate damage. A growing spectrum of intrinsic defects are recognized to affect myeloid cell function, including the recently recognized and common clinical entity known as CHIP, wherein age-associated somatic mutations drive the emergence of hyperinflammatory myeloid cell populations. Whereas myeloid cells and their effector cytokines are the targets of several existing therapies for kidney disease, ongoing developments in our understanding will drive new therapies to emerge.
S.M. Moran, M.J. Rauh, and C. Vlasschaert report being employed by Queen’s University. All other authors have nothing to disclose.
This work was supported by the Government of Canada Canadian Institutes of Health Research grant 201911FBD-433120-DRA-CEDA-251523 and Physicians’ Services Incorporated Foundation grant RT8-2021.
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