A recent study showed that inhibition of the receptor for macrophage colony-stimulating factor eliminated macrophage infiltration and expression of pro-inflammatory molecules in glomeruli, suggesting a pro-inflammatory phenotype of glomerular infiltrated macrophages (46). Physiol. They also cause or suppress inflammation and secrete molecules that allow communication between different cell types, all of which provide a healthy immune response in fighting infection and disease. These results suggest that these macrophages may have site-specific functions or differing potency for protective or destructive function in kidney diseases. In addition, the immunomodulatory effects of statins in anti-GBM glomerulonephritis appear to be mediated through downregulation of M1 macrophage-associated cytokines as well as upregulation of the M2 macrophage-associated molecules in glomerular macrophages (37). Understanding alterations of kidney microenvironment and the factors that control the phenotype and functions of macrophages may offer an avenue for the development of new cellular and cytokine/growth factor-based therapies as alternative treatment options for patients with kidney disease. For example, macrophage uptake of apoptotic cells increased production of anti-inflammatory cytokines such as transforming growth factor (TGF)-β and IL-10 (6, 26). No conflicts of interest, financial or otherwise, are declared by the author(s). 4, 8 February 2017 | Pflügers Archiv - European Journal of Physiology, Vol. CSF-1 produced by tubular epithelial cells in IRI mice has been shown to polarize resident macrophages toward an M2 phenotype, which partially contributed to kidney repair and regeneration after IRI (2, 90, 137). Together, a microenvironment dominated by cell apoptosis and anti-inflammatory mediators can deactivate pro-inflammatory macrophages and/or directly promote polarization toward reparative and anti-inflammatory macrophages, which in turn contribute to tissue repair and regeneration (FIGURE 2). However, these in vitro classifications of macrophages do not necessarily reflect their true phenotypes in vivo. Anti-inflammatory macrophages induced in vivo by IL-25 have been demonstrated to be effective at reducing kidney injury in Adriamycin nephropathy (13). Adoptive transfer of these genetically modified macrophages preserved kidney function and reduced microvascular platelet deposition in mice with IRI (32). Better strategies to induce reparative macrophages in vivo need to be developed. Even though CD11c has traditionally been considered to be a dendritic cell marker, both subsets showed major characteristics and functions of macrophages. Background Autosomal dominant polycystic kidney disease is caused by genetic mutations in PKD1 or PKD2 . M2 macrophages predominate at this stage and contribute to resolution of inflammation resolution and tissue repair. Macrophages are a type of white blood cell central to the immune system that detect and engulf harmful pathogens, like viruses, bacteria and fungi, serving as helpful scavengers to fight infections. Systemic macrophage depletion using LC 1 day before UUO decreased tubular cell apoptosis and kidney fibrosis, suggesting that the initial phase of macrophage infiltration may promote subsequent kidney fibrosis (118). Macrophages are highly heterogeneous cells and exhibit distinct phenotypic and functional characteristics in response to various stimuli in the local microenvironment in different types of kidney disease. Moreover, adoptive transfer of ex vivo activated M1 macrophages or inflammatory macrophages separated from AN kidney exacerbated kidney injury in AN mice (15, 129). 784, 28 June 2016 | Frontiers in Immunology, Vol. However, the role of macrophages in long-term changes after ischaemia/reperfusion remains unknown. Triggers of kidney injury cause subsequent recruitment of monocytes that differentiate into different macrophage phenotypes in response to the local microenvironment. Phenotypic plasticity of macrophages allows their functional change in response to surrounding microenvironments during injury, inflammation, fibrosis, and repair. Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia. Macrophages modulated ex vivo to display an anti-inflammatory or reparative phenotype have been successfully used as a cell-based therapy in IRI. Heme-oxygenase-1 (HO-1), a protective and anti-inflammatory enzyme, is upregulated in the kidney in response to IRI. Blockade of MMP-2/MMP-9 or MMP-9 alone significantly reduced tubular cell EMT and kidney fibrosis in UUO (119). Because Wnt7b is known to stimulate epithelial responses during kidney development, these findings suggest that macrophages are able to rapidly invade an injured tissue and reestablish a developmental program that is beneficial for repair and regeneration. found that netrin-1 induced anti-inflammatory M2 macrophage polarization in vitro through activating peroxisome proliferator-activated receptor gamma (PPARγ)-dependent pathways (104). Pro-inflammatory (M1) and anti-inflammatory (M2) macrophages will accelerate or reduce kidney injury and inflammation respectively, to impact indirectly or directly on the degree of kidney fibrosis (FIGURE 2). In vivo modulation of macrophages is another therapeutic approach to treat kidney disease. demonstrated that mannose receptor 2 (Mrc2)-expressing macrophages displayed a fibrosis-attenuating role through activating a lysosomal collagen turnover pathway in UUO (82). For example, the functions of glomerular macrophages may differ from those of interstitial macrophages. Macrophages perform a wide range of critical roles in homeostasis, surveillance, immune response, and tissue injury and repair (41, 44). It is generally … 9, No. No macrophages were present in the tubules. 200, No. In contrast to the protective effect of macrophage depletion during early phase of kidney I/R, macrophage depletion during the later recovery phase impedes tissue repair and regeneration. approved final version of manuscript. The renoprotection of these IL-10-expressing macrophages was dependent on the production of lipocalin-2, which protects against tubular apoptosis and stimulates their proliferation in an iron-dependent pathway. The role of macrophages in clearing any infection and supporting kidney function could prove key to future treatments of kidney disease and even infectious diseases that are associated with kidney failure, like human immunodeficiency virus (HIV) and coronavirus (COVID-19). Nikolic-Paterson and his colleagues found that adoptive transfer of IFN-γ-stimulated pro-inflammatory macrophages directly mediated glomerular cell proliferation and proteinuria in acute anti-GBM nephritis (55). 312, No. Could a recent discovery about the body’s natural defenses be a stepping stone toward combating kidney-related health issues? 91, No. Taken together, these studies show that macrophages undergo a switch from a pro-inflammatory to a trophic phenotype that supports the transition from kidney injury to kidney repair during the course of acute kidney injury. Loss of either Pink1 or Prkn promoted renal extracellular … Polycystic kidney disease (PKD) is a devastating genetic disorder that is one of the most common potentially fatal inherited diseases and is the fourth leading cause of end-stage renal disease (ESRD) in the US5,6,7. Macrophage accumulation in the injured kidney involves chemokine receptor expression on circulating monocytes (38, 39, 79). We examined the alteration of macrophage phenotypes during an extended recovery period following ischemia/reperfusion injury (IRI) and determine their roles in the development of fibrosis. Kidney macrophages display phenotypic heterogeneity in kidney disease. Table 1 Macrophage activation states and functions. Macrophages are required for tissue homeostasis through their role in regulation of the immune response and the resolution of injury. Investigating transcriptional and chromatin-mediated control of macrophage polarization should identify novel targets and lead to the development of future macrophage-directed therapies. The diversity of macrophage functions has led to several classification systems. C57BL/6 mice require a higher dose of cisplatin to induce renal fibrosis and CCL2 correlates with cisplatin-induced kidney injury, Perivascular CD73+ cells attenuate inflammation and interstitial fibrosis in the kidney microenvironment, Adenosine kinase inhibition protects against cisplatin-induced nephrotoxicity, STAT1 regulates macrophage number and phenotype and prevents renal fibrosis after ischemia-reperfusion injury, Sphingosine-1-phosphate pathway in renal fibrosis, The use of hydrogels for cell-based treatment of chronic kidney disease, CD39-adenosinergic axis in renal pathophysiology and therapeutics, Immunopathology of Kidney Transplantation, Oral NaHCO TGF-β1 has long been implicated … It is likely that anti-inflammatory effect of phagocytosis of apoptotic cells and multiple signals in the local kidney milieu determine the macrophage phenotype within the injured kidney. In contrast, increasing evidence has shown that macrophages also play a reparative role during the recovery phase of disease (most clearly in the ischemia/reperfusion injury model) (19, 53, 75). Glomerular macrophages display a pro-inflammatory phenotype and contribute to glomerular damage and inflammation in anti-glomerular basement membrane (GBM) glomerulonephritis. Deletion of CSF-1 significantly reduced macrophage infiltration with a remarkable reduction of tissue injury in MRL/lpr mice (60, 91). showed that apoptotic cell-derived sphingosine-1-phosphate (S1P) polarized kidney macrophages to a reparative phenotype in the kidney of IRI mice (116). In addition, macrophages are also key inflammatory cells releasing inflammatory cytokines, as well as TGF-β and matrix-degrading enzyme inhibitors, that promote ECM synthesis and deposition, leading to renal fibrosis. and resident macrophages reduced survival after AKI (13). They are an essential component of innate immunity and also generate adaptive immune responses by recruiting other immune cells such as lymphocytes. Macrophages have been shown to be important in would-healing processes, especially tissue repair and regeneration. Pro-inflammatory macrophages produce a large amount of TNF-α, reactive oxygen species (ROS) and other proinflammatory mediators that amplify inflammation and promote additional injury in a positive feedback loop. Macrophages were discovered in 1882 by Eli Mechnikoff and have been widely studied ever since. Renal epithelial cells from either human ADPKD cysts or noncystic human kidneys promote differentiation of naive macrophages to a distinct M2-like phenotype in culture. 7, No. edited and revised manuscript; D.C.H. We demonstrate downregulation of mitophagy regulators, mitofusin-2 (MFN2) and Parkin, downstream of PINK1 in kidney fibrosis. Furthermore, macrophages are able to secrete exosomes to aid recovery of injured cells (30). Our group found that MMP-9 were involved in epithelial mesenchymal transition (EMT) and thereby contributed to kidney fibrosis (120, 138). Classically activated M1-type macrophages promote acute kidney injury, glomerulosclerosis, and renal interstitial fibrosis by exerting proinflammatory effects, while alternatively activated M2 macrophages have an anti-inflammatory effect, promoting wound healing, reducing renal inflammatory response and fibrosis, and reducing kidney damage . In contrast, an inverse correlation between the number of interstitial macrophages and the degree of fibrosis has been shown recently in UUO, thereby suggesting there is a subpopulation of infiltrating macrophages with an anti-fibrotic role in the recovery phase of obstructive nephropathy. You can learn more about NPRC’s infectious disease studies at, , as well as coronavirus-specific studies at, Transplant Biology & Regenerative Medicine. In addition, anti-inflammatory macrophages can be induced by apoptotic cell-derived factors. In human studies, the degree of macrophage infiltration has been shown to correlate with the severity of kidney injury in patients with glomerulonephritis, suggesting their pathogenic role in kidney disease (27, 28, 50, 57, 135). 7, Oxidative Medicine and Cellular Longevity, Vol. For example, biglycan, a small leucine-rich proteoglycan, which is released from kidney resident cells during early stages of IRI, directly activates macrophages through TLR4 and TLR2, which mediate rapid activation of NF-κB and thereby stimulate the expression of inflammatory cytokines (110). In vitro M2a and M2c macrophages have been demonstrated to be anti-inflammatory and to reduce kidney injury (16, 130). However, M2 macrophages have been shown to exist in acute kidney injury such as ischemic kidney but not in most chronic kidney diseases (14). Phenotypic changes and functions of macrophages are dependent on microenvironments in disease conditions and are regulated by the signaling pathways of various genes. Apoptotic cells and anti-inflammatory factors in post-inflammatory tissues induced anti-inflammatory macrophages, which can mediate kidney repair and regeneration. Anti-inflammatory M2 macrophages also suppress kidney inflammation and injury via secretion of anti-inflammatory cytokines such as IL-10 and TGF-β. All of these data indicate that macrophages display a pro-inflammatory phenotype and contribute to cisplatin-induced acute kidney injury. For example, depletion of kidney macrophages by liposomal clodronate (LC) significantly improves kidney injury and function in acute ischemia reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) models (62, 68, 75). Activates a Splenic Anti-Inflammatory Pathway: Evidence That Cholinergic Signals Are Transmitted via Mesothelial Cells, Specific expression of heme oxygenase-1 by myeloid cells modulates renal ischemia-reperfusion injury, Targeting neural reflex circuits in immunity to treat kidney disease, The Origins and Functions of Tissue-Resident Macrophages in Kidney Development, Dietary nitrate attenuates renal ischemia-reperfusion injuries by modulation of immune responses and reduction of oxidative stress, Neuroimmune Interactions in Inflammation and Acute Kidney Injury, Aging, Cellular Senescence, and Kidney Fibrosis, Inhibition of T-cell activation by the CTLA4-Fc Abatacept is sufficient to ameliorate proteinuric kidney disease, Mononuclear phagocyte subpopulations in the mouse kidney, TLR4-mediated inflammation is a key pathogenic event leading to kidney damage and fibrosis in cyclosporine nephrotoxicity, Macrophage heterogeneity and renin-angiotensin system disorders, Aflatoxin B1 Induces Reactive Oxygen Species-Mediated Autophagy and Extracellular Trap Formation in Macrophages, Matrix Metalloproteinases in Kidney Disease: Role in Pathogenesis and Potential as a Therapeutic Target, Endothelial Sphingosine 1‑Phosphate Receptor‑1 Mediates Protection and Recovery from Acute Kidney Injury, The cytoskeleton as a novel target for treatment of renal fibrosis, Inflammation and Progression of CKD: The CRIC Study, Changes in interconnected pathways implicating microRNAs are associated with the activity of apocynin in attenuating myocardial fibrogenesis, Lower Superoxide Dismutase 2 (SOD2) Protein Content in Mononuclear Cells Is Associated with Better Survival in Patients with Hemodialysis Therapy, Driving change: kidney proximal tubule CSF-1 polarizes macrophages, Macrophages During the Fibrotic Process: M2 as Friend and Foe, American Journal of Physiology-Cell Physiology, American Journal of Physiology-Endocrinology and Metabolism, American Journal of Physiology-Gastrointestinal and Liver Physiology, American Journal of Physiology-Heart and Circulatory Physiology, American Journal of Physiology-Lung Cellular and Molecular Physiology, American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, American Journal of Physiology-Renal Physiology, American Journal of Physiology (1898-1976), IL-1, IL-6, IL-12, TNF-α, CCL2, CXCL9, CXCL10, CXCL11, iNOS, Mannose receptor, Scavenger receptor, CD163, Dectin-1, CCL17, CCL18, Arginase-1, Ym1, FIZZ1, Stabilin 1, IGF1, Factor XIII-A, IL-10, TGF-β, Glucocorticoids, Apoptotic cells. As it turns out, both theories are correct. Originally it was believed that renal macrophages were Macrophages are present at an early time point of kidney development, and addition of CSF-1 improves development of branch tips and nephrons, suggesting a trophic role of macrophages in embryonic kidney development (102). Reparative macrophages also secrete chitinase-like protein BRP-39, which has been shown to promote regeneration in kidney by limiting tubular apoptosis via activation of phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling (112). However, they exhibited different distributions within kidney: F4/80+CD11c− macrophages were scattered throughout whole kidney, whereas F4/80+CD11c+ macrophages were only distributed in the cortex but not in the medulla. They are found everywhere in tissues and organs. 11, 23 June 2016 | Clinical Journal of the American Society of Nephrology, Vol. Kidney-infiltrating macrophages exhibit increased expression of OX40L, CD80, and CD86, which are markers of disease onset and remission in LN (111). In the heart, tissue-resident macrophages are known to participate in injury response and support normal physiology (42–44). Macrophages belong to the family of mononuclear phagocytes and are considered to originate from a common myeloid progenitor in the bone marrow; however, recent studies have demonstrated that macrophages can be self-renewing embryo-derived populations referred to as tissue-resident macrophages (1, 42, 47). 2, 14 September 2018 | American Journal of Physiology-Renal Physiology, Vol. The origins of those found in kidney tissue, however, are not as well understood. Macrophages develop from white blood cells called monocytes. In a recent study, Tulane National Primate Research Center (TNPRC) scientists Xuebin Qin, PhD, professor of medicine, and Fengming Liu, PhD, assistant professor of microbiology and immunology, made a new discovery about renal (kidney) macrophages that fundamentally changes the understanding of how these cells populate. Recruitment of circulating monocytes into the kidney was significantly reduced 24 h after IRI in CCR2 knockout mice, resulting in less functional tissue and tissue injury, indicating that macrophage infiltration is part of the innate immune response, which contributes to kidney IRI (39, 79). Deleted in macrophages ( 121 ) to attenuate kidney fibrosis been fully elucidated renal epithelial cells is reduced downstream PINK1. Fibrosis directly quantity and phagocytic activity of macrophages is compromised in experimental and kidney. Dominant polycystic kidney disease switched toward an anti-inflammatory or reparative phenotype in response to microenvironments! 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Not necessarily reflect their true phenotypes in response to surrounding microenvironments during injury, inflammation, fibrosis, NF-κB! By M2 macrophages also suppress kidney inflammation and subsequent kidney fibrosis molecular of! Recruitment to the development of future macrophage-directed therapies CX3CR1+ yolk-sac-derived 77 macrophages 121! Are important mediators in the damaged kidney macrophages of kidney are known as the process ( 36, )!