In vivo modulation of macrophages is another therapeutic approach to treat kidney disease. Macrophages modulated ex vivo to display an anti-inflammatory or reparative phenotype have been successfully used as a cell-based therapy in IRI. When macrophages are inducibly ablated from the injured kidney, the canonical Wnt pathway response in kidney epithelial cells is reduced. 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). 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. Proc Natl Acad Sci U S A. 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. 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). 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). 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. However, M2 macrophages have been shown to exist in acute kidney injury such as ischemic kidney but not in most chronic kidney diseases (14). Adoptive transfer of netrin-1-treated macrophages suppressed inflammation and protected against kidney injury in IRI mice (105). 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). Interestingly, IFNγ-stimulated M1 macrophages injected during the repair phase switched toward an anti-inflammatory M2 phenotype within the kidney. 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 . 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). Direct evidence for a pathogenic role of macrophages was shown by our group by the protection of macrophages depletion in AN against kidney functional and structural injury (128). 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). During the early phase of tissue damage, the kidney interstitial microenvironment is dominated by micro-organism-derived pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), as well as pro-inflammatory cytokines, which promote full activation of the pro-inflammatory M1 macrophage. Macrophages, also known as the big eaters, are specialized immune cells that play a central role in many inflammatory processes in the human body. You can learn more about NPRC’s infectious disease studies at this link, as well as coronavirus-specific studies at this link. Renal macrophages are the most well studied inflammatory cell in the kidney and their involvement in cyst formation has been reported in different animal models and patients with cystic kidney disease. 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. Apoptotic cells, anti-inflammatory cytokines, as well as growth factors are likely to predominate in the induction of anti-inflammatory macrophages (FIGURE 2). In addition, anti-inflammatory macrophages can be induced by apoptotic cell-derived factors. These tissue-specific macrophage subpopulations can change their phenotype and function in response to local microenvironmental signals during tissue infection or injury (94). For example, depletion of kidney macrophages using LC at the time of initial injury protected against kidney injury in IRI mice, suggesting that macrophages play a critical role in mediating tissue injury (21, 62). 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). 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). Kidney macrophages display heterogeneity, which has been defined by different surface markers. Interstitial inflammation is an important feature of cystic kidney disease. 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 is a prominent feature of the innate immune response to kidney injury. It is likely that anti-inflammatory (M2) macrophages coexist in small numbers or are absent due to a persistently inflammatory kidney microenvironment. 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. Macrophage accumulation in the injured kidney involves chemokine receptor expression on circulating monocytes (38, 39, 79). “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. Macrophages are known to be major producers of transforming growth factor-β1 (TGF-β1), especially in the setting of phagocytosis of apoptotic cells. and Y.W. 132, No. Ramesh found that inhibition of p38 MAPK activation led to decreased production of TNF-α in macrophages and resulted in less kidney injury in cisplatin nephrotoxicity (103). Their roles in inflammation and the molecular effectors of macrophage function have been difficult to decipher. 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 vitro cisplatin induced enhanced expression of TLRs and their associated signaling molecules in macrophages (121). HO-1-overexpressing macrophages displayed an anti-inflammatory phenotype, with increased phagocytosis of apoptotic cells and increased IL-10 production (32). It is generally … Copyright 2020 National Primate Research Centers - All Rights Reserved. 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). When administered at the time of I/R injury, IL-10-transfected macrophages trafficked to the post-ischemic kidney and reduced tubular injury and pro-inflammatory cytokine production within the kidney (64). Here we show, using the kidney as a model, that the Wnt pathway ligand Wnt7b is produced by macrophages to stimulate repair and regeneration. 784, 28 June 2016 | Frontiers in Immunology, Vol. 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 possible existence and importance of site-specific macrophages is not clear. 4, 1 April 2017 | American Journal of Physiology-Renal Physiology, Vol. 4, 14 September 2018 | Clinical Science, Vol. During development in the womb, immune cells called macrophages go to the kidneys, and they remain there for life. Kidney macrophages display phenotypic heterogeneity in kidney disease. Macrophages were virtually never seen in the interstitium, except in areas of scarring. Tissue-resident macrophages have unique tissue-specific functions in maintaining homeostasis and resolving inflammation. However, these proposed phenotypes need to be defined in various kidney disease models. 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). approved final version of manuscript. In vitro coculture studies indicate that macrophage phenotypic change was induced by tubular cell-derived factors. For example, one study revealed that suppression of macrophage recruitment in osteopontin-knockout mice reduces tubulointerstitial fibrosis during the recovery process of IRI (100). Soc. edited and revised manuscript; D.C.H. Galectin-3 produced by kidney resident macrophages drives myofibroblast accumulation/activation and promotes kidney fibrosis in UUO (49). 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). 3-4, 23 February 2017 | Frontiers in Cellular and Infection Microbiology, Vol. Nishida and colleagues demonstrated that interstitial macrophages display an anti-fibrotic role at day 14, but not at day 5, after UUO (95). In the kidneys, these cells react very sensitively to tissue damage and adapt very quickly to dynamic changes in their environment. 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. As mentioned above, macrophages are the predominant infiltrating cells that accumulate in the outer medulla of the postischemic kidney. Strikingly, depletion of kidney macrophages by LC suppressed intraglomerular proliferative lesions and abrogated crescent formation in NZB/NZW F1 mice, suggesting that M2b macrophages mediate a dysregulated “tissue repair” program in poly (I:C)-induced LN. Molecules in macrophages, from inflammation and cause substantial tissue damage and adapt very quickly to dynamic signals from local... With the advent of modern genetic tools and mouse models of human disease, great into. 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