macrophages of kidney are known as
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They are found everywhere in tissues and organs. The pathogenic role of pro-inflammatory macrophages in LN has been revealed by blockade of CCL2 or CCR2 and by depletion of colony stimulating factor-1 (CSF-1) in MRL/lpr mice (70, 91, 99, 122). The anti-inflammatory macrophage-derived reparative molecules in IRI mice are poorly known. The possible existence and importance of site-specific macrophages is not clear. Even though CD11c has traditionally been considered to be a dendritic cell marker, both subsets showed major characteristics and functions of macrophages. 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). 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. Anti-inflammatory macrophages induced in vivo by IL-25 have been demonstrated to be effective at reducing kidney injury in Adriamycin nephropathy (13). 2, 14 September 2018 | American Journal of Physiology-Renal Physiology, Vol. The M1/M2 nomenclature mirrors the T helper 1 (Th1)-Th2 polarization of T cells. Alternatively, macrophages also can be modulated into a protective phenotype to reduce kidney injury in kidney disease. The anti-fibrotic role of interstitial macrophages at a later stage (day 14) of UUO was confirmed by using cyclophosphamide-mediated macrophage depletion (96). In addition, adoptive transfer of in vitro modulated M1 macrophages aggravated kidney injury, indicating their pathogenic role in IRI (75). Introduction: Acute kidney injury (AKI) is a major risk factor in the development of chronic kidney disease (CKD). Taken together, current data suggest a phase-dependent balance of profibrotic and antifibrotic effects of macrophages in UUO. Table 1 Macrophage activation states and functions. The mechanisms underlying the anti-fibrotic role of interstitial macrophages in UUO have been studied recently. Macrophages have been shown to be important in would-healing processes, especially tissue repair and regeneration. Monocytes are produced in bone marrow and circulate in the blood anywhere from one to three days. Most notably, bacterial cell wall components such as lipopolysaccharide, flagellin, and cytosine-guanine rich (CpG) microbial oligodeoxynucleotides, collectively known as pathogen-associated molecular patterns (PAMPs), … 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). They are an essential component of innate immunity and also generate adaptive immune responses by recruiting other immune cells such as lymphocytes. However, these proposed phenotypes need to be defined in various kidney disease models. Macrophages are large, round cells that contain a central round nucleus and have abundant clear, often vacuolated, cytoplasm. 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). In contrast, the uptake of apoptotic cells and anti-inflammatory cytokines drive macrophage polarization toward an anti-inflammatory M2 phenotype, which in turn promotes renal repair through secretion of trophic factors such as Wnt7b, heme-oxygenase-1 (HO-1), and chitinase-like protein BRP-39. 8, 23 May 2017 | Current Pathobiology Reports, Vol. Several other studies confirmed that macrophages are involved in the kidney repair after IRI in that macrophage ablation by either LC or diphtheria toxin 48–72 h after IRI resulted in persistent kidney injury (67, 83, 127). This review summarizes the role of macrophages with different phenotypes in kidney injury, inflammation, and fibrosis in various acute and chronic kidney diseases. Kidney macrophages display phenotypic heterogeneity in kidney disease. The diverse roles of macrophages, from inflammation and injury to tissue repair and remodeling, are not fully understood. When cultured in vitro Mϕs may be activated by a range of stimuli. 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 . Heme-oxygenase-1 (HO-1) is an anti-inflammatory enzyme that has been shown to be beneficial in various models of kidney injury (10, 66). 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). Monocytes and macrophages are demonstrated in greater numbers within the kidney by antisera to muramidase than to a-l-antitrypsin. Steroid-based treatments appear to reduce kidney inflammation and injury by promoting anti-inflammatory macrophages in vivo (58). Pro-inflammatory macrophages also produce metalloproteases (MMPs) to enable their migration through basement membranes and interstitial ECM networks (117). The most common form of the disease, autosomal dominant PKD (ADPKD) affects up to 1 in 500 and costs $2 billion/year to care for those afflicted. Kidney macrophages form a functional unit with endothelial cells, rapidly taking up IC transported to them by virtue of their unique position and morphology. Macrophage infiltration correlated with kidney structural and functional injury in this model, suggesting that the macrophages may have been responsible for glomerular and interstitial injury (77). Macrophages were virtually never seen in the interstitium, except in areas of scarring. Macrophages play a special role in the onset of several diseases, including acute and chronic kidney injuries. The phenotypic switch of macrophages is determined by microenvironment during the course of acute and chronic kidney disease. Also M1/M2 phenotypes do not fully mirror macrophage phenotypes in vivo. 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). 5, No. Adriamycin nephropathy (AN) is a rodent model of chronic kidney disease that mirrors human primary focal segmental glomerulosclerosis. Could a recent discovery about the body’s natural defenses be a stepping stone toward combating kidney-related health issues? 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). MCP-1 and CXCL1 (known mediators of AKI), and also GMCSF and IL-1β were increased in AKI and decreased in LEC-treated AKI but not AKI in CD11b-DTR or CD11c-DTR mice. For the M2 phenotype, others including C/EBPβ, PPARγ, IRF, and the STAT family have been reported to be important (73). In vitro M2a and M2c macrophages have been demonstrated to be anti-inflammatory and to reduce kidney injury (16, 130). In contrast, macrophages at the later stage of repair may become profibrotic or fibrolytic to respectively induce or resolve kidney fibrosis directly. Persistent inflammatory and fiborotic factors in chronic kidney disease promote renal fibrosis. 2, 16 April 2018 | The Journal of Immunology, Vol. However, the mechanisms linking AKI to CKD remain unclear. Increased expression of CSF-1 in tubular epithelial cells has been noted in LN. Macrophages were discovered in 1882 by Eli Mechnikoff and have been widely studied ever since. 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). They also showed that embryo-derived renal macrophages have a stronger immune response than their bone marrow-derived counterparts. In the kidneys, these cells react very sensitively to tissue damage and adapt very quickly to dynamic changes in their environment. Union Physiol. 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. 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. However, existence of profibrotic and fibrolytic macrophages has yet to be demonstrated unequivocally in vivo CKD. 11, 23 June 2016 | Clinical Journal of the American Society of Nephrology, Vol. These tissue-specific macrophage subpopulations can change their phenotype and function in response to local microenvironmental signals during tissue infection or injury (94). The origins of those found in kidney tissue, however, are not as well understood. 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). In addition, kidney fibrosis in murine obstructive nephropathy is attenuated by depletion of monocyte lineage in CD11b-DTR mice, but not dendritic cells in CD11c-DTR mice (87, 115). Ranganathan et al. Free full text . 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. Two well defined phenotypes are commonly referred to as classically activated macrophages (M1 macrophages), produced by exposure to LPS or IFN-γ, and alternatively activated macrophages (M2 macrophages), produced by Th2 cytokines such as IL-4 and IL-10 (Table 1) (43). 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 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. No macrophages were present in the tubules. Macrophages are found in normal kidney and in increased numbers in diseased kidney, where they act as key players in renal injury, inflammation, and fibrosis. Pro-inflammatory macrophages can be targeted to reduce inflammation and fibrosis in kidney diseases. They found that the angiotensin II type 1 receptor (Agtr1) on macrophage functions to attenuate kidney fibrosis in vivo. The existence of fibrolytic macrophages has yet to be demonstrated unequivocally in kidney disease. Fibrosis may occur, depending on the severity of injury and whether pathogenic factors continue to be expressed. Interestingly, IFNγ-stimulated M1 macrophages injected during the repair phase switched toward an anti-inflammatory M2 phenotype within the kidney. 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. Proc Natl Acad Sci U S A. Depletion of macrophages during kidney repair is associated with sustained kidney inflammation and injury, and impaired tubular cell proliferation and tissue repair (67, 75). Galectin-3 produced by kidney resident macrophages drives myofibroblast accumulation/activation and promotes kidney fibrosis in UUO (49). Because Wnt7b is known to stimulate epithelial responses during kidney development, these ﬁndings suggest that macrophages are The diversity of macrophage functions has led to several classification systems. 4, 1 September 2016 | Archives of Toxicology, Vol. It is likely that anti-inflammatory (M2) macrophages coexist in small numbers or are absent due to a persistently inflammatory kidney microenvironment. You can learn more about NPRC’s infectious disease studies at this link, as well as coronavirus-specific studies at this link. For example, the functions of glomerular macrophages may differ from those of interstitial macrophages. Traditionally, macrophages have been recognized as key players that contribute to kidney fibrosis. 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). These fetal-generated macrophages self-maintain throughout adulthood and are only partially replaced by bone marrow-derived circulating … Similarly, administration of LC selectively depleted both F4/80+ macrophages and F4/80+ dendritic cells, but not F4/80− dendritic cells, in mice with UUO, resulting in attenuated tubular apoptosis and kidney fibrosis and decreased levels of the pro-fibrotic cytokine TGF-β (68). Using a new rapid cell ablation (destruction) technique created by Qin, the team discovered that in a mouse model, half of renal macrophages originate during the embryonic state and the other half derive from bone marrow. In addition, regulatory T cells further promote the anti-inflammatory macrophage phenotype via release of IL-10 and TGF-β and by suppressing effector T cells (81). They have a large, single nucleus that is often kidney-shaped. Monocytes infiltrate the injured kidney shortly after neutrophils, differentiate into macrophages, and contribute to early tubular injury (3). performed experiments; Q.C. Reduction of interstitial inflammation and tissue injury in AN mice by blockade of CCR1, CCL2, or CCL5 was associated with a remarkable reduction of macrophage infiltration, suggesting macrophages play a critical role in development of AN (125, 132, 140). The same strategy can be used to define transcriptional control elements in kidney macrophages. Inflammatory macrophages secrete TNF-α, IL-1β, IL-6, IL-23, reactive oxygen species (ROS), and other pro-inflammatory mediators and further amplify intrarenal inflammation and injury in a positive feedback loop (FIGURE 2), as has been discussed in ischemia-reperfusion injury (36, 61, 75), cisplatin nephrotoxicity (18, 103), anti-GBM glomerulonephritis (5, 55), lupus nephritis (7, 97, 98), renal allograft injury (63, 89), and adriamycin nephropathy (15, 129). 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). Due to progressive injury and persistent inflammation, M1 macrophages persistently surround sites of damaged tissue. 4, 8 February 2017 | Pflügers Archiv - European Journal of Physiology, Vol. Early studies showed that macrophage accumulation in glomeruli is a direct response to the deposition of antibody in anti-GBM glomerulonephritis, and inhibition of macrophage accumulation by anti-macrophage serum significantly prevented progression of glomerulonephritis, thereby implicating macrophages as mediators of glomerular injury and inflammation (51, 52). Furthermore, when Wnt7b is somatically deleted in macrophages, … M1 macrophages may convert to M2 macrophages in response to tissue factors within the kidney during the recovery phase. Mutations in PKD1 or PKD2 of LN ( 17 ) of immune complex in the presence of … resident. Regulating the balance of profibrotic and fibrolytic macrophages has yet to be important in would-healing processes, tissue! 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