The word macrophage comes from the Greek meaning ‘large eater’. A newly suggested classification may more closely reflect phenotypes of in vivo macrophages; in this classification, macrophages have been defined as pro-inflammatory, anti-inflammatory, fibrotic, and fibrolytic (6). Lee found that depletion of macrophages at the time of IRI (when M1 macrophages are predominant) attenuated kidney injury, whereas depletion during the repair phase (when M2 macrophages are predominant) delayed kidney repair (75). The persistence of macrophages is associated with tubulointerstitial fibrosis and progression of chronic kidney disease. 312, No. The same strategy can be used to define transcriptional control elements in kidney macrophages. CCL2/CCR2 signaling is critical for monocyte recruitment to the site of inflammation. Scientists have long known the origins of different types of macrophages found in the brain, gut, heart and liver. In summary, kidney macrophage origins are diverse: the early kidney is colonized by yolk sac-derived macrophages, but the resident macrophages in the early postnatal kidney are predominantly derived from EMP- and HSC-derived monocytic precursors (Figure 2). Anti-inflammatory M2 macrophages also suppress kidney inflammation and injury via secretion of anti-inflammatory cytokines such as IL-10 and TGF-β. Monocytes/macrophages are able to fuse with other cells for tissue regeneration and also to transform into other cell types, including neuronal, endothelial, and muscle cells (48, 126, 139). TGF-β1 has long been implicated … 4, 1 April 2017 | American Journal of Physiology-Renal Physiology, Vol. 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. The expression of HO-1 by kidney macrophages has been shown to improve the outcome in kidney IRI, whereas downregulation of HO-1 expression in kidney macrophages of aging mice resulted in an increased susceptibility to kidney IRI (31, 45). Macrophages are highly heterogeneous cells that are divided into subpopulations based on their distinct functions and anatomical location, including as examples Langerhans cells, Kupffer cells, microglial cells, and osteoclasts (101). Physiol. Alkali supplementation as a therapeutic in chronic kidney disease: what mediates protection? M1 macrophages produce a great amount and a great number of pro-inflammatory mediators and mediate antimicrobial defence and antitumour immunity. Macrophages were discovered in 1882 by Eli Mechnikoff and have been widely studied ever since. kidney macrophages, for example, represent a distinct macrophage subset that can promote angiogenesis and repair in the damaged kidney 35. Recent studies revealed that kidney F4/80hi macrophages exhibited a unique hybrid activation phenotype with expression of both pro-inflammatory and anti-inflammatory mediators in chronic LN, indicating that the standard M1/M2 paradigm for macrophages is insufficient to explain chronic inflammation in lupus nephritis (9, 109). showed that apoptotic cell-derived sphingosine-1-phosphate (S1P) polarized kidney macrophages to a reparative phenotype in the kidney of IRI mice (116). C-C motif chemokine receptor 2 (CCR2), the main chemokine receptor for monocyte chemoattractant protein-1 (MCP-1/CCL2), is expressed on a subset of monocytes. 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). and Y.W. Here we show, using the kidney as a model, that the Wnt pathway ligand Wnt7b is produced by macrophages to stimulate repair and regeneration. They found that the angiotensin II type 1 receptor (Agtr1) on macrophage functions to attenuate kidney fibrosis in vivo. Introduction: Acute kidney injury (AKI) is a major risk factor in the development of chronic kidney disease (CKD). In vitro cisplatin induced enhanced expression of TLRs and their associated signaling molecules in macrophages (121). 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). However, existence of profibrotic and fibrolytic macrophages has yet to be demonstrated unequivocally in vivo CKD. Macrophages were virtually never seen in the interstitium, except in areas of scarring. Monocytes are produced in bone marrow and circulate in the blood anywhere from one to three days. The mechanisms by which macrophages are polarized to an anti-inflammatory phenotype in the post-ischemic kidney are not well understood. Could a recent discovery about the body’s natural defenses be a stepping stone toward combating kidney-related health issues? In the kidneys, these cells react very sensitively to tissue damage and adapt very quickly to dynamic changes in their environment. Methods In these studies, we used conditional Pkd1 mice to test the hypothesis that macrophage … 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. Blockade of MMP-2/MMP-9 or MMP-9 alone significantly reduced tubular cell EMT and kidney fibrosis in UUO (119). 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). When macrophages are inducibly ablated from the injured kidney, the canonical Wnt pathway response in kidney epithelial cells is reduced. 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). 784, 28 June 2016 | Frontiers in Immunology, Vol. Due to progressive injury and persistent inflammation, M1 macrophages persistently surround sites of damaged tissue. The diverse roles of macrophages, from inflammation and injury to tissue repair and remodeling, are not fully understood. Kidney Macrophages Show Evidence of Activation and Correlate Numerically With Disease Outcomes. Macrophages (MΦ) are highly heterogeneous cells that exhibit distinct phenotypic and functional characteristics depending on their microenvironment and the disease type and stage. Macrophages modulated ex vivo to display an anti-inflammatory or reparative phenotype have been successfully used as a cell-based therapy in IRI. For example, TNF-α has a critical role in mediating the kidney injury. When cultured in vitro Mϕs may be activated by a range of stimuli. 7, No. 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. For example, adipose tissue macrophages can convert themselves from a wound-healing phenotype to a classically activated phenotype during obesity-associated inflammation (84, 85). Inflammatory monocytes infiltrate to the site of tissue injury shortly after neutrophils, where they differentiate into macrophages and are polarized into pro-inflammatory macrophages (M1) by various inflammatory mediators, such as IFN-γ, that are released from neighboring inflammatory cells, including neutrophils, NK cells, and T effector cells (predominantly Th1/17). showed that absence of scavenging receptors on uPAR−/− macrophages led to delayed clearance of pro-fibrotic molecules, resulting in kidney fibrosis in late-stage UUO (136). 315, No. 2010 Mar 2; 107(9): 4194–4199. 2, 7 April 2017 | American Journal of Physiology-Renal Physiology, Vol. Macrophage depletion by clodronate microspheres resulted in greatly reduced TNF-α and IL-1β release in anti-GBM glomerulonephritis, suggesting that inflammatory macrophages mediated glomerular damage through release of pro-inflammatory cytokines (24). A: acute kidney injury triggers recruitment of neutrophils and natural-killer (NK) cells within several hours of tissue injury. 316, No. The accumulation of senescent cells during aging and the senescence-associated secretory phenotype, which leads to inflammaging, is known to be deleterious and account for progressive organ dysfunction. somatically deleted in macrophages, repair of injury is greatly diminished. These fetal-generated macrophages self-maintain throughout adulthood and are only partially replaced by bone marrow-derived circulating … Kidney fibrosis could be a consequence of kidney injury and inflammation, which involves macrophage infiltration. When M1 macrophages were adoptively transferred early after injury, they switched to an M2 phenotype within the kidney during the later recovery phase. prepared figures; Q.C. You can learn more about NPRC’s infectious disease studies at this link, as well as coronavirus-specific studies at this link. This review summarizes the role of macrophages with different phenotypes in kidney injury, inflammation, and fibrosis in various acute and chronic kidney diseases. However, whether in vitro macrophages can be modulated to become fibrolytic to reduce fibrosis is unknown. However, the role of macrophages in long-term changes after ischaemia/reperfusion remains unknown. Macrophages are required for tissue homeostasis through their role in regulation of the immune response and the resolution of injury. Recently, Anders and Ryu proposed four types of in vivo macrophages, defined according to their predominant roles in various phases of kidney disease, namely pro-inflammatory, anti-inflammatory, profibrotic, and fibrolytic macrophages (6). However, the repair role and relevant molecules of kidney-resident macrophages after ischemic injury remain unresolved. These questions need further investigation. López-Guisa et al. Adriamycin nephropathy (AN) is a rodent model of chronic kidney disease that mirrors human primary focal segmental glomerulosclerosis. In this sense, tubule interstitial nephritis (TIN) represents an underestimated insult, which can be triggered by different stimuli and, in the absence of a proper regulation, can lead to fibrosis deposition. Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia. All of these data indicate that macrophages display a pro-inflammatory phenotype and contribute to cisplatin-induced acute kidney injury. In addition, anti-inflammatory macrophages can be induced by apoptotic cell-derived factors. 6, 9 March 2016 | Journal of the American Society of Nephrology, Vol. They also showed that embryo-derived renal macrophages have a stronger immune response than their bone marrow-derived counterparts. 91, No. Monocytes are the largest type of white blood cell. The alternatively activated macrophages can be subdivided further into at least three subgroups: M2a macrophages induced by IL-4 and/or IL-13, M2b macrophages induced by immune complexes with LPS or IL-1β, and M2c macrophages induced by IL-10, TGF-β, or glucocorticoids (88). 75 Results and Discussion: 76 Two complementary strategies were used to fate-map CSF1R+, and CX3CR1+ yolk-sac-derived 77 macrophages (Fig. 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). Kidney macrophages form a functional unit with endothelial cells, rapidly taking up IC transported to them by virtue of their unique position and morphology. They have a large, single nucleus that is often kidney-shaped. These results suggest that targeting innate immune response signaling pathways of macrophages could be a possible therapeutic strategy against kidney fibrosis. Moreover, early or late treatment with the JNK inhibitor improved kidney function and attenuated glomerular and tubulointerstitial damage in the chronic anti-GBM model (35, 86). Sola et al. Adoptive transfer of these genetically modified macrophages preserved kidney function and reduced microvascular platelet deposition in mice with IRI (32). More importantly, the applicability of these classification systems, namely the M1/M2 paradigm or the newer system four macrophage phenotypes, needs to be examined in human kidney disease. 14, No. The implications of this discovery are important because while the kidneys help control the volume of blood in the body and maintain the proper concentrations of proteins and electrolytes, they are also subject to infection and disease. Macrophages are well-known for their pathogenic role in kidney fibrosis. 800 Cell 166, August 11, 2016 (NTN), macrophage depletion results in less severe renal pathology (Chalmers et al., 2015), as does inhibition of FcgR signaling on myeloid cells (Sharp et al., 2013). Finally, injection of the Wnt pathway regulator Dkk2 enhances the repair process and suggests a therapeutic option. found that kidney macrophages expressed pro-inflammatory markers during the initial phase of IRI, whereas macrophages displayed an alternatively activated phenotype during the repair phase (75). 14 December 2020 | American Journal of Physiology-Renal Physiology, Vol. M2 macrophages predominate at this stage and contribute to resolution of inflammation resolution and tissue repair. More recently, macrophages have been classified as classically activated macrophages (M1 macrophages), wound-healing macrophages (also known as M2a), and regulatory macrophages (also known as M2c) on the basis of their fundamental activation and function (92). These findings suggest that F4/80+ macrophages/dendritic cells, but not CD11c+ DCs play a pivotal role in the development of kidney fibrosis following ureteral obstruction in mice. Cisplatin-treated macrophages were more susceptible to different TLR ligands, such as PAMPs and DAMPs in injured kidney, produced large amounts of nitric oxide and pro-inflammatory cytokines, and demonstrated increased activation of NF-κB and mitogen-activated protein kinases (MAPK) (18). 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). Macrophages, also known as the big eaters, are specialized immune cells that play a central role in many inflammatory processes in the human body. 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. 3, 24 June 2019 | American Journal of Physiology-Renal Physiology, Vol. Transcription factors including JNK, MAPK, and NF-κB have been demonstrated to be involved in defining the M1 phenotype. More recently, macrophages have been classified as classically activated macrophages (M1 macrophages), wound-healing macrophages (also known as M2a), and regulatory macrophages (also known as M2c) on the basis of their fundamental activation and function . found that targeting IL-18 derived from activated macrophages by a neutralizing binding protein protected against the development of AN, with less interstitial inflammation, tissue injury, and kidney dysfunction (133). Macrophages acts as sentinel cells; they have a role in destroying bacteria, protozoa and tumour cells, and release substances that act upon other immune cells. FIGURE 1.Phase-dependent macrophage phenotypic change during the progress of kidney diseases. However, these in vitro classifications of macrophages do not necessarily reflect their true phenotypes in vivo. 27, No. In the presence of … Acute kidney injury caused by ischemia reperfusion or cytotoxic drugs triggers a prominent infiltrate of neutrophils and natural killer cells within hours of tissue injury (72, 78, 93, 104). However, increased evidence has suggested an anti-fibrotic role of infiltrating macrophages in obstructive nephropathy. Macrophages (also known as leucocytes) are specialized white blood cells of the immune system and play a vital part in innate (inborn) immunity and immune responses of the body. In contrast, M2 macrophages have anti-inflammatory functions and are involved in parasite containment, wound healing, and fibrosis (94, 114). The peritoneal M2 macrophages effectively alleviated the renal injury and inflammatory response in mice with ischaemia-reperfusion injury (IRI) and promoted the PTEC proliferation in vivo and in vitro. In the heart, tissue-resident macrophages are known to participate in injury response and support normal physiology (42–44). Zhang et al. 1A). ©2015 Int. Increased expression of CSF-1 in tubular epithelial cells has been noted in LN. MΦ are distributed throughout normal and diseased kidney tissue, where they have been recognized as key factors in renal fibrosis. 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. 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. You can learn more about NPRC’s infectious disease studies at, , as well as coronavirus-specific studies at, Transplant Biology & Regenerative Medicine. However, the mechanisms linking AKI to CKD remain unclear. Therefore, depletion of macrophages before or during the early stages of IRI reduces kidney injury and improves tissue repair. The possible existence and importance of site-specific macrophages is not clear. These studies indicate that targeting glomerular macrophages could be a potential approach to treat glomerulonephritis. “These findings advance our current understanding of tissue-resident macrophages and may lead to promising new directions for the development of new therapeutics for kidney diseases,” explained Qin. A pathogenic role of macrophages has been demonstrated by depletion or repletion of resident kidney macrophages in different types of experimental kidney diseases (55, 62, 68, 75, 129). FIGURE 2.Distinct macrophage subsets regulating the balance of renal injury, inflammation, repair, and fibrosis. 4, 1 September 2016 | Archives of Toxicology, Vol. 9, No. conception and design of research; Q.C. Macrophages and their associated inflammatory cytokines promote cyst progression; however, transcription factors within macrophages that control cytokine production and cystic disease are unknown. 9, European Journal of Pharmacology, Vol. Sci./Am. No macrophages were present in the tubules. These tissue-specific macrophage subpopulations can change their phenotype and function in response to local microenvironmental signals during tissue infection or injury (94). Subsequently, small numbers of Th2 cells and Tregs are recruited into kidney to regulated local immune responses. 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). The anti-inflammatory macrophage-derived reparative molecules in IRI mice are poorly known. S1P-dependent neutrophil gelatinase-associated lipocalin (NGAL/Lcn-2) produced by these macrophages was identified as a regenerative mediator enhancing tubular epithelial cell proliferation in the repair phase of IRI. Until now, researchers hadn’t known if these macrophages had traveled from elsewhere in the body or if they were produced during embryonic development. Braga and colleagues found that M2 macrophages contributed to kidney fibrosis of UUO in a MyD88-dependent manner (11). It is noted that these studies on EMT were performed in vitro, whereas the occurrence of EMT in in vivo renal fibrosis remains subject to argument (54, 59, 74). Join our community and be among the first to learn more about our efforts to improve human health worldwide. Kidney macrophages display phenotypic heterogeneity in kidney disease. It is generally … Furthermore, macrophages are able to secrete exosomes to aid recovery of injured cells (30). However, administration of diphtheria toxin abolished the protective effects of LC-mediated macrophage ablation in IRI mice, suggesting that there may be a protective population of mononuclear phagocytes in the kidney in the aftermath of LC treatment (33). Interstitial inflammation is an important feature of cystic kidney disease. These data suggest that kidney macrophages change their phenotype in response to dynamic signals from the local kidney environment. Also M1/M2 phenotypes do not fully mirror macrophage phenotypes in vivo. In addition, Galectin-3 and TGF-β produced by M2 macrophages promote kidney fibrosis directly. These studies suggest that the JNK pathway is essential for macrophage-mediated kidney injury in anti-GBM glomerulonephritis. 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. KEY WORDS-Monocyte, glomerulus, a-l-antitrypsin, muramidase. We have identified two major subsets of macrophages, which are F4/80+CD11c− and F4/80+CD11c+ cells in murine kidney (15). The diversity of macrophage functions has led to several classification systems. However, these proposed phenotypes need to be defined in various kidney disease models. Recently, Wyburn et al. Phenotypic changes and functions of macrophages are dependent on microenvironments in disease conditions and are regulated by the signaling pathways of various genes. 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). Pro-inflammatory macrophages contribute to the initiation and progression of kidney disease by secretion of pro-inflammatory mediators and interaction with kidney resident cells. In experimental models of kidney fibrosis, the mannose receptor 2 (Mrc2) (also known as urokinase receptor–associated protein and Endo180), which is expressed by ^15% of interstitial myofibroblasts and macrophages, significantly reduces fibrosis severity compared with mice with genetic Mrc2 deficiency. 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. The mechanism underlying the pro-fibrotic role of macrophages in UUO has not been fully elucidated. 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