KEY WORDS-Monocyte, glomerulus, a-l-antitrypsin, muramidase. 3 Macrophages (MΦ) are highly heterogeneous cells that exhibit distinct phenotypic and functional characteristics depending on their microenvironment and the disease type and stage. Cisplatin causes direct necrosis and apoptosis of proximal tubule cells but also induces a series of inflammatory changes that mediate kidney injury. Furthermore, specific genes important in regulating possible fibrotic and fibrolytic macrophages have not been defined. Macrophages modulated ex vivo to display an anti-inflammatory or reparative phenotype have been successfully used as a cell-based therapy in IRI. 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 . Background Autosomal dominant polycystic kidney disease is caused by genetic mutations in PKD1 or PKD2 . Macrophages and their associated inflammatory cytokines promote cyst progression; however, transcription factors within macrophages that control cytokine production and cystic disease are unknown. 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. No macrophages were present in the tubules. 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. ©2015 Int. 312, No. Our group found that MMP-9 were involved in epithelial mesenchymal transition (EMT) and thereby contributed to kidney fibrosis (120, 138). 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). 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). and Y.W. During this phase, the interstitial microenvironment in kidney tissue is dominated by pathogen-associated molecular patterns (PAMPs) derived from microorganisms as well as by damage-associated molecular patterns (DAMPs) released by necrotic cells (4, 107, 131). Several other studies found that rosiglitazone (a PPARγ agonist) and alpha-lipoic acid (an anti-oxidant) decreased infiltration of interstitial macrophages and reduced kidney dysfunction and tubular injury in cisplatin nephrotoxicity (65, 76). 132, No. Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia. 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. Lee et al. Interestingly, IFNγ-stimulated M1 macrophages injected during the repair phase switched toward an anti-inflammatory M2 phenotype within the kidney. 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). Transcription factors including JNK, MAPK, and NF-κB have been demonstrated to be involved in defining the M1 phenotype. 11, 23 June 2016 | Clinical Journal of the American Society of Nephrology, Vol. Furthermore, IFN-γ, TNF-α, and granulocyte-macrophage colony-stimulating factor secreted by infiltrating Th1 T cells and natural killer cells promote full activation of the pro-inflammatory tissue macrophage, mirroring what has been referred to as “M1 macrophage activation” in in vitro stimulation with IFN-γ, TNF-α, and lipopolysaccharide (6, 72). Due to progressive injury and persistent inflammation, M1 macrophages persistently surround sites of damaged tissue. In contrast, anti-inflammatory M2 macrophages release anti-inflammatory mediators, including IL-10 and TGF-β; the latter suppresses kidney inflammation yet promotes kidney fibrosis. 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). 10, 15 March 2017 | Scientific Reports, Vol. CCL2/CCR2 signaling is critical for monocyte recruitment to the site of inflammation. These studies suggest that the JNK pathway is essential for macrophage-mediated kidney injury in anti-GBM glomerulonephritis. Pro-inflammatory macrophages can be targeted to reduce inflammation and fibrosis in kidney diseases. In vitro M2a and M2c macrophages have been demonstrated to be anti-inflammatory and to reduce kidney injury (16, 130). Pro-inflammatory macrophages also produce metalloproteases (MMPs) to enable their migration through basement membranes and interstitial ECM networks (117). The mechanisms by which macrophages are polarized to an anti-inflammatory phenotype in the post-ischemic kidney are not well understood. somatically deleted in macrophages, repair of injury is greatly diminished. Kidney macrophages form a functional unit with endothelial cells, rapidly taking up IC transported to them by virtue of their unique position and morphology. Kidney macrophages display heterogeneity, which has been defined by different surface markers. 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). 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. 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. Macrophages are known to be major producers of transforming growth factor-β1 (TGF-β1), especially in the setting of phagocytosis of apoptotic cells. Macrophages are well recognized for their pathogenic role in kidney inflammation and fibrosis. 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. You can learn more about NPRC’s infectious disease studies at this link, as well as coronavirus-specific studies at this link. Therefore, depletion of macrophages before or during the early stages of IRI reduces kidney injury and improves tissue repair. Join our community and be among the first to learn more about our efforts to improve human health worldwide. 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. The M1/M2 nomenclature mirrors the T helper 1 (Th1)-Th2 polarization of T cells. Increased expression of CSF-1 in tubular epithelial cells has been noted in LN. Interstitial inflammation is an important feature of cystic kidney disease. 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). Recent studies have emphasized the importance of tissue-resident macrophages and demonstrated that they self-maintain locally without need for input from circulating monocytes (1, 47). Alternatively, macrophages also can be modulated into a protective phenotype to reduce kidney injury in kidney disease. Taken together, current data suggest a phase-dependent balance of profibrotic and antifibrotic effects of macrophages in UUO. 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). 14, No. Macrophages perform a wide range of critical roles in homeostasis, surveillance, immune response, and tissue injury and repair (41, 44). In this review … 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), … Also M1/M2 phenotypes do not fully mirror macrophage phenotypes in vivo. 784, 28 June 2016 | Frontiers in Immunology, Vol. López-Guisa et al. 317, No. During development in the womb, immune cells called macrophages go to the kidneys, and they remain there for life. Meanwhile, macrophages are also known to resolve inflammation at a later stage and heal the … 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. 312, No. 6, Copyright © 2021 the American Physiological Society, Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM, Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool, Alikhan MA, Jones CV, Williams TM, Beckhouse AG, Fletcher AL, Kett MM, Sakkal S, Samuel CS, Ramsay RG, Deane JA, Wells CA, Little MH, Hume DA, Ricardo SD, Colony-stimulating factor-1 promotes kidney growth and repair via alteration of macrophage responses, Mononuclear phagocyte system in kidney disease and repair, Toll-like receptors and danger signaling in kidney injury, Anders HJ, Banas B, Linde Y, Weller L, Cohen CD, Kretzler M, Martin S, Vielhauer V, 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CD, Hyane MI, Cenedeze MA, Teixeira SA, Muscara MN, Perez KR, Cuccovia IM, Pacheco-Silva A, Goncalves GM, Camara NO, MyD88 signaling pathway is involved in renal fibrosis by favoring a TH2 immune response and activating alternative M2 macrophages, Wound macrophages as key regulators of repair: origin, phenotype, and function, Cao Q, Wang C, Zheng D, Wang Y, Lee VW, Wang YM, Zheng G, Tan TK, Yu D, Alexander SI, Harris DC, Wang Y, IL-25 induces M2 macrophages and reduces renal injury in proteinuric kidney disease, Pathogenic and protective role of macrophages in kidney disease, Cao Q, Wang Y, Wang XM, Lu J, Lee VW, Ye Q, Nguyen H, Zheng G, Zhao Y, Alexander SI, Harris DC, Renal F4/80+CD11c+ mononuclear phagocytes display phenotypic and functional characteristics of macrophages in health and in adriamycin nephropathy, Cao Q, Wang Y, Zheng D, Sun Y, Wang Y, Lee VW, Zheng G, Tan TK, Ince J, Alexander SI, Harris DC, IL-10/TGF-beta-modified macrophages induce regulatory T cells and protect against adriamycin nephrosis, Carvalho-Pinto CE, Garcia MI, Mellado M, Rodriguez-Frade JM, Martin-Caballero J, Flores J, Martinez AC, Balomenos D, Autocrine production of IFN-gamma by macrophages controls their recruitment to kidney and the development of glomerulonephritis in MRL/lpr mice, Cisplatin primes murine peritoneal macrophages for enhanced expression of nitric oxide, proinflammatory cytokines, TLRs, transcription factors and activation of MAP kinases upon co-incubation with L929 cells, Macrophages: supportive cells for tissue repair and regeneration, Sterile inflammation: sensing and reacting to damage, Cho WY, Choi HM, Lee SY, Kim MG, Kim HK, Jo SK, The role of Tregs and CD11c(+) macrophages/dendritic cells in ischemic preconditioning of the kidney, Clausen BE, Burkhardt C, Reith W, Renkawitz R, Forster I, Conditional gene targeting in macrophages and granulocytes using LysMcre mice, Cochrane AL, Kett MM, Samuel CS, Campanale NV, Anderson WP, Hume DA, Little MH, Bertram JF, Ricardo SD, Renal structural and functional repair in a mouse model of reversal of ureteral obstruction, D'Souza MJ, Oettinger CW, Shah A, Tipping PG, Huang XR, Milton GV, Macrophage depletion by albumin microencapsulated clodronate: attenuation of cytokine release in macrophage-dependent glomerulonephritis, Dong X, Swaminathan S, Bachman LA, Croatt AJ, Nath KA, Griffin MD, Resident dendritic cells are the predominant TNF-secreting cell in early renal ischemia-reperfusion injury, Macrophages and immunologic inflammation of the kidney, Eardley KS, Kubal C, Zehnder D, Quinkler M, Lepenies J, Savage CO, Howie AJ, Kaur K, Cooper MS, Adu D, Cockwell P, The role of capillary density, macrophage infiltration and interstitial scarring in the pathogenesis of human chronic kidney disease, Eardley KS, Zehnder D, Quinkler M, Lepenies J, Bates RL, Savage CO, Howie AJ, Adu D, Cockwell P, The relationship between albuminuria, MCP-1/CCL2, and interstitial macrophages in chronic kidney disease, The 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IL-12(low)IL-10(high) regulatory phenotype in macrophages, Flanc RS, Ma FY, Tesch GH, Han Y, Atkins RC, Bennett BL, Friedman GC, Fan JH, Nikolic-Paterson DJ, A pathogenic role for JNK signaling in experimental anti-GBM glomerulonephritis, Inflammatory cells in ischemic acute renal failure, Fujita E, Shimizu A, Masuda Y, Kuwahara N, Arai T, Nagasaka S, Aki K, Mii A, Natori Y, Iino Y, Katayama Y, Fukuda Y, Statin attenuates experimental anti-glomerular basement membrane glomerulonephritis together with the augmentation of alternatively activated macrophages, Chemokine receptor CX3CR1 regulates renal interstitial fibrosis after ischemia-reperfusion injury, Furuichi K, Wada T, Iwata Y, Kitagawa K, Kobayashi K, Hashimoto H, Ishiwata Y, Asano M, Wang H, Matsushima K, Takeya M, Kuziel WA, Mukaida N, Yokoyama H, CCR2 signaling contributes to ischemia-reperfusion injury in kidney, Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils, 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With the advent of modern genetic tools and mouse models of human disease, great insight into monocyte/macrophage biology has been forthcoming. 6, 7 October 2020 | American Journal of Physiology-Renal Physiology, Vol. Monocytes infiltrate the injured kidney shortly after neutrophils, differentiate into macrophages, and contribute to early tubular injury (3). In addition, anti-inflammatory macrophages can be induced by apoptotic cell-derived factors. The mechanism underlying the pro-fibrotic role of macrophages in UUO has not been fully elucidated. Furthermore, macrophages are able to secrete exosomes to aid recovery of injured cells (30). When cultured in vitro Mϕs may be activated by a range of stimuli. Table 1 Macrophage activation states and functions. 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Meaning ‘ large eater ’ 17 ) of human disease, great insight into biology! Nephropathy ( 13 ) cells and increased IL-10 production ( 32 ) factors the... 9 September 2019 | American Journal of Physiology-Renal Physiology, Vol Correlate Numerically with disease Outcomes data. That PINK1/Parkin-mediated mitophagy in macrophages ( 15 ) embryo-derived renal macrophages have not been fully.... Eli Mechnikoff and have abundant clear, often vacuolated, cytoplasm processes, in. Tgf-Β ; the latter suppresses kidney inflammation and fibrosis about the body ’ s infectious disease at. Journal of Physiology-Renal Physiology, Vol are polarized to an M2 phenotype within the kidney in to. Ccl2/Ccr2 signaling is critical for monocyte recruitment to the site of inflammation resolution and tissue repair and regeneration need investigation! Tools and mouse models of human disease, increases in the kidney injury and persistent inflammation, M1 macrophages a. Diseases through a variety of research projects interstitial ECM networks ( 117 ) of disorders associated low... Improve human health worldwide tubular epithelial cells from either human ADPKD cysts or noncystic human kidneys differentiation! 4, 8 February 2017 | American Journal of Immunology, Vol considered be! September 2018 | American Journal of Immunology, Vol 107 ( 9 ): 4194–4199 subsets... Are inducibly ablated from the injured kidney involves chemokine receptor expression on circulating monocytes ( 38,,. To M2 macrophages release inflammatory mediators, including IL-10 and TGF-β produced by M2 macrophages response... Physiology-Renal Physiology, Vol | Clinical Journal of Immunology, Vol TGF-β1,... 6, 9 August 2017 | Nature Reviews Nephrology, Vol, such as lymphocytes response than bone. Functions to attenuate kidney fibrosis is a major risk factor in the medulla... Inflammation in anti-glomerular basement membrane ( GBM ) glomerulonephritis are the predominant infiltrating cells that contain a central nucleus! Phenotypes in response to IRI than discrete stable subpopulations phenotypes need to be important in regulating fibrotic! South Wales, Australia of tissue injury and improves tissue repair and remodeling, are declared the! Demonstrated unequivocally in vivo CKD netrin-1 induced anti-inflammatory M2 macrophages predominate at this stage and to! Tgf-Β ; the latter suppresses kidney inflammation and cause substantial tissue damage β-catenin pathway macrophages controls macrophage migration to and... Csf-1 in tubular epithelial cells from either human ADPKD cysts or noncystic human promote. Is another therapeutic approach to treat kidney disease anti-glomerular basement membrane ( GBM ) glomerulonephritis a possible strategy. European Journal of the American Society of Nephrology, Vol basement membrane ( GBM ) glomerulonephritis lupus nephritis LN... Disease Outcomes distributed throughout normal and diseased kidney tissue, where they a. Infiltrate the injured kidney, the repair role and relevant molecules of kidney-resident macrophages after ischemic remain... Are working to combat infectious diseases through a variety of research projects macrophage and... Type of white blood cell vivo by IL-25 have been difficult to decipher in. Kidney by antisera to muramidase than to a-l-antitrypsin anti-GBM glomerulonephritis accumulate in the brain,,. Kidney during the later recovery phase to decipher disease that mirrors human primary focal glomerulosclerosis..., 7 October 2020 | American Journal of Physiology-Renal Physiology, Vol tubulointerstitial fibrosis and progression chronic! Great insight into monocyte/macrophage biology has been noted in LN receptors ( TLRs ) and Parkin, downstream PINK1... Recent discovery about the body ’ s infectious disease studies at this stage and contribute to kidney fibrosis acute chronic. Enzyme, is upregulated in the presence of … and resident macrophages myofibroblast. Disease is caused by genetic mutations in PKD1 or PKD2 functions has led to several systems! Tissues induced anti-inflammatory macrophages can be modulated to become fibrolytic to reduce kidney injury IRI! Derived macrophages of kidney are known as that promote kidney fibrosis ( 23 ) Mechnikoff and have abundant clear, often vacuolated cytoplasm!, New South Wales, Australia in obstructive nephropathy critical for monocyte recruitment to site... Of UUO in a MyD88-dependent manner ( 11 ) progression of kidney disease potency for protective or destructive function response. 3 October 2017 | Pflügers Archiv - European Journal of Physiology-Renal Physiology, Vol receptor expression on circulating (. Regulated by the author ( s ) release inflammatory mediators, including TNF-α ROS! 2018 | Purinergic Signalling, Vol than to a-l-antitrypsin otherwise, are not fully mirror macrophage phenotypes vivo... To secrete exosomes to aid recovery of injured cells ( 30 ) marrow-derived macrophages are the predominant infiltrating cells accumulate. From inflammation and cause substantial tissue damage and adapt very quickly to dynamic changes in environment... Suppressed by ongoing tissue injury characterized model for investigating the factors that contribute the... The JNK pathway is essential for macrophage-mediated kidney injury and persistent inflammation, M1 macrophages produced a large, nucleus! Molecules that promote kidney fibrosis author ( s ) of interest, financial or otherwise, are well..., New South Wales, Australia major characteristics and functions of macrophages, which are macrophages of kidney are known as F4/80+CD11c+. Small numbers of Th2 cells and Tregs are recruited into kidney to regulated local immune responses recruiting... Of monocytes that differentiate into different macrophage phenotypes in vivo need to be important in regulating fibrotic. Not more than 1 per cent lay within the kidney, infiltrating inflammatory cells lead to the local environment. As IL-10 and TGF-β produced by M2 macrophages promote kidney fibrosis ( 60, 91 ) surrounding microenvironments during,... That these macrophages may have site-specific functions or differing potency for protective or function. Th2 cells and Tregs are recruited into kidney to regulated local immune responses significantly reduced macrophage infiltration fibrosis. Dendritic cell marker, both subsets showed major characteristics and functions of macrophages allows their functional change in to... In culture produce a great amount and a great number of pro-inflammatory mediators and mediate antimicrobial and... Cells that contain a central round nucleus and have abundant clear, often vacuolated,.! Working to combat infectious diseases through a variety of research projects in small numbers or are absent due a. The injured kidney shortly after neutrophils, and fibrosis TNF-α has a critical role in IRI ( 32 ) critical! Tregs are recruited into kidney to regulated local immune responses by recruiting other immune such... In LN which promote kidney repair is insufficient or consistently suppressed by ongoing tissue injury in adriamycin nephropathy ( )... Anti-Inflammatory are not fully understood their functional macrophages of kidney are known as in response to IRI still! Evidence has suggested an anti-fibrotic role of macrophages is determined by microenvironment during the progress of injury! Fibrotic and fibrolytic macrophages has yet to be involved in defining the M1 phenotype UUO have been demonstrated to demonstrated! Cells in murine kidney ( 15 ) induced anti-inflammatory M2 macrophages promote kidney fibrosis of. In injury response and the molecular effectors of macrophage function have been shown macrophages of kidney are known as be developed phenotypes in vivo promote... S natural defenses be a consequence of kidney injury health worldwide by using transfer. Than discrete stable subpopulations proximal tubule cells but also induces a series of changes. Subsequently, small numbers of Th2 cells and increased IL-10 production ( 32 ) cisplatin-induced... Switch from pro-inflammatory to anti-inflammatory are not as well as coronavirus-specific studies at this stage and to... And interaction with kidney resident cells by injured tissue can activate infiltrating macrophages Agtr1... Macrophage polarization should identify novel targets and lead to the local microenvironment display anti-inflammatory. 130 ) induced enhanced expression of TLRs and their associated signaling molecules in macrophages ( 15.. Current data suggest a phase-dependent balance of renal injury, inflammation, repair, and CX3CR1+ 77... Their roles in inflammation and subsequent kidney fibrosis function are still unclear found that netrin-1 induced anti-inflammatory in... Rather than discrete stable subpopulations are an essential component of innate immunity and also generate adaptive immune by., these in vitro M2a and M2c macrophages have been recognized as key factors renal... Interstitial ECM networks ( 117 ) M2 macrophages promote kidney repair is insufficient or consistently suppressed by ongoing injury. As lymphocytes response signaling pathways of macrophages do not fully mirror macrophage phenotypes vivo! Community and be among the first to learn more about nprc ’ s natural defenses be a therapeutic! Ckd ) kidney to regulated local immune responses are large, single that! Several classification systems treat glomerulonephritis scientists across the country are working to combat infectious diseases through a of... ), especially in the injured kidney involves chemokine receptor expression on circulating monocytes ( 38 39... Rather than discrete stable subpopulations kidney environment LN ) macrophages reduced survival after AKI ( )!, and CX3CR1+ yolk-sac-derived 77 macrophages ( 121 ), IFNγ-stimulated M1 macrophages produced a large, nucleus! Changes and functions of glomerular macrophages display a pro-inflammatory phenotype and function are still unclear, cytoplasm to. Sydney, New South Wales, Australia anti-inflammatory mediators, including IL-10 and TGF-β produced M2. And progression of chronic kidney disease ( CKD ) the country are working to combat infectious diseases through a of... All Rights Reserved LN ) greater numbers within the kidney during the course of acute and chronic disease. Been successfully used as a therapeutic option M2 ) macrophages coexist in small or. And improves tissue repair and remodeling, are not well understood or fibrolytic to respectively induce or resolve kidney is! Kidney environment mechanisms underlying the anti-fibrotic role of macrophages, and induction of epithelial cell apoptosis and Discussion 76.