Macrophage heterogeneity, phenotypes, and roles in renal fibrosis
2014; Elsevier BV; Volume: 4; Issue: 1 Linguagem: Inglês
10.1038/kisup.2014.4
ISSN2157-1724
AutoresQi Cao, Yiping Wang, David C.H. Harris,
Tópico(s)Phagocytosis and Immune Regulation
ResumoMacrophages (MΦ) are highly heterogeneous cells that exhibit distinct phenotypic and functional characteristics depending on their microenvironment and the disease type and stage. MΦ are distributed throughout normal and diseased kidney tissue, where they have been recognized as key factors in renal fibrosis. Recent studies have identified switch of phenotype and diverse roles for MΦ in several murine models of kidney disease. In this review, we discuss macrophage heterogeneity and their involvement in renal fibrosis. Macrophages (MΦ) are highly heterogeneous cells that exhibit distinct phenotypic and functional characteristics depending on their microenvironment and the disease type and stage. MΦ are distributed throughout normal and diseased kidney tissue, where they have been recognized as key factors in renal fibrosis. Recent studies have identified switch of phenotype and diverse roles for MΦ in several murine models of kidney disease. In this review, we discuss macrophage heterogeneity and their involvement in renal fibrosis. Macrophages (MΦ) comprise a heterogeneous population of cells, with diverse functions and phenotypic plasticity. MΦ belong to the family of mononuclear phagocytes and are known to have a central role in promoting progression or resolution of renal inflammation and fibrosis.1.Nelson P.J. Rees A.J. Griffin M.D. et al.The renal mononuclear phagocytic system.J Am Soc Nephrol. 2012; 23: 194-203Crossref PubMed Scopus (193) Google Scholar However, lack of specific markers to differentiate dendritic cells from MΦ has generated confusion regarding their exact function in kidney diseases.2.Ferenbach D. Hughes J. Macrophages and dendritic cells: what is the difference?.Kidney Int. 2008; 74: 5-7Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar Moreover, MΦ are highly heterogeneous cells whose subsets exhibit varying activities in different kidney diseases. The existing simplistic definitions of MΦ, based largely on in vitro observations, are not sufficient to allow conclusions about the role of sub-populations of MΦ. In light of the importance of accurate characterization of MΦ subsets, recently we have re-examined their classification and identified four subsets of renal mononuclear phagocytes of which two subsets displayed MΦ-like properties and accounted for the great majority (>83.5%) of murine renal mononuclear phagocyte (unpublished data). Of these two subsets, one expressed the typical MΦ marker F4/80 without CD11c, and the other also expressed CD11c, a classical marker for dendritic cells. In healthy and diseased kidney, both subsets displayed typical MΦ-like properties including morphology, in vitro functions, expression of specific surface markers and transcription factors, and ontogeny. However, the role of these two subsets in renal fibrosis is unknown. Although MΦ were recognized commonly for their pathogenic role in renal inflammation and fibrosis, MΦ also have critical roles in wound healing, in tissue remodeling and repair, and in immune regulation. MΦ in vitro have been classified into classically activated macrophages (M1) and alternatively activated macrophages (M2), which have been subdivided further into M2a, M2b, and M2caccording to their response to different modulators.3.Martinez F.O. Sica A. Mantovani A. et al.Macrophage activation and polarization.Front Biosci. 2008; 13: 453-461Crossref PubMed Scopus (2268) Google Scholar,4.Ricardo S.D. van Goor H. Eddy A.A. Macrophage diversity in renal injury and repair.J Clin Invest. 2008; 118: 3522-3530Crossref PubMed Scopus (562) Google Scholar However, this classification does not reflect adequately their true phenotypes in in vivo tissue environments. Recently, Anders and Ryu5.Anders H.J. Ryu M. Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis.Kidney Int. 2011; 80: 915-925Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar have proposed four types of in vivo MΦ, defined according to their predominant roles in phases of wound healing, namely pro-inflammatory, anti-inflammatory, profibrotic and fibrolytic MΦ. MΦ of M1- and M2-like (i.e., pro-inflammatory and anti-inflammatory) phenotypes have been demonstrated in acute ischemia-reperfusion injury and unilateral ureteral obstruction (UUO) models.6.Jo S.K. Sung S.A. Cho W.Y. et al.Macrophages contribute to the initiation of ischaemic acute renal failure in rats.Nephrol Dial Transplant. 2006; 21: 1231-1239Crossref PubMed Scopus (261) Google Scholar, 7.Lee S. Huen S. Nishio H. et al.Distinct macrophage phenotypes contribute to kidney injury and repair.J Am Soc Nephrol. 2011; 22: 317-326Crossref PubMed Scopus (619) Google Scholar, 8.Nishida M. Fujinaka H. Matsusaka T. et al.Absence of angiotensin II type 1 receptor in bone marrow-derived cells is detrimental in the evolution of renal fibrosis.J Clin Invest. 2002; 110: 1859-1868Crossref PubMed Scopus (119) Google Scholar, 9.Lopez-Guisa J.M. Cai X. Collins S.J. et al.Mannose receptor 2 attenuates renal fibrosis.J Am Soc Nephrol. 2012; 23: 236-251Crossref PubMed Scopus (49) Google Scholar Phenotypic switch of MΦ from M1 to M2 has been shown accompanying a change in the microenvironment.7.Lee S. Huen S. Nishio H. et al.Distinct macrophage phenotypes contribute to kidney injury and repair.J Am Soc Nephrol. 2011; 22: 317-326Crossref PubMed Scopus (619) Google Scholar,10.Zhang M.Z. Yao B. Yang S. et al.CSF-1 signaling mediates recovery from acute kidney injury.J Clin Invest. 2012; 122: 4519-4532Crossref PubMed Scopus (237) Google Scholar Lee et al.7.Lee S. Huen S. Nishio H. et al.Distinct macrophage phenotypes contribute to kidney injury and repair.J Am Soc Nephrol. 2011; 22: 317-326Crossref PubMed Scopus (619) Google Scholar found that kidney MΦ expressed pro-inflammatory markers during the initial phase of ischemia-reperfusion injury, whereas MΦ displayed an alternatively activated phenotype during the repair phase. When M1 MΦ were adoptively transferred early after injury, they switched to an M2 phenotype within the kidney during the later recovery phase. Colony-stimulating factor-1 has been reported to induce resident MΦ expansion and direct them toward an M2 phenotype, which mediated renal tubule epithelial regeneration after acute kidney injury.10.Zhang M.Z. Yao B. Yang S. et al.CSF-1 signaling mediates recovery from acute kidney injury.J Clin Invest. 2012; 122: 4519-4532Crossref PubMed Scopus (237) Google Scholar Moreover, C-C chemokine receptor 5 and Kruppel-like factor 4 have been identified as key regulators controlling M1 vs. M2 MΦ phenotypes, respectively, in kidney transplantation and wound healing.11.Dehmel S. Wang S. Schmidt C. et al.Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long-term renal allograft outcome.Eur J Immunol. 2010; 40: 267-278Crossref PubMed Scopus (32) Google Scholar,12.Liao X. Sharma N. Kapadia F. et al.Kruppel-like factor 4 regulates macrophage polarization.J Clin Invest. 2011; 121: 2736-2749Crossref PubMed Scopus (490) Google Scholar In our previous studies, adoptive transfer of M1 MΦ, but not resting MΦ, increased renal injury and fibrosis in murine adriamycin nephropathy (AN), highlighting the importance of MΦ activation status in causing renal injury.13.Wang Y. Cao Q. Zheng G. et al.By homing to the kidney, activated macrophages potently exacerbate renal injury.Am J Pathol. 2008; 172: 1491-1499Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar In contrast, M2a MΦ protected against renal structural and functional injury in immunodeficient (severe combined immunodeficiency) mice with AN.14.Wang Y. Wang Y.P. Zheng G. et al.Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease.Kidney Int. 2007; 72: 290-299Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar Recently, we compared the effectiveness of different subsets of M2 MΦ in protecting against renal injury in AN mice (Table 1).15.Cao Q. Wang Y. Zheng D. et al.IL-10/TGFβ-modified macrophages induce regulatory T cells and protect against murine ariamycin nephrosis.J Am Soc Nephrol. 2010; 21: 933-942Crossref PubMed Scopus (200) Google Scholar,16.Lu J.Y. Cao Q. Zheng D. et al.Discrete functions of M and M macrophage subsets determine their relative efficacy in treating chronic kidney disease.Kidney Int. 2013; 84: 745-755Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar Both transfused M2a and M2c MΦ significantly reduced glomerulosclerosis, tubular atrophy, interstitial expansion, and renal fibrosis in AN mice. M2a and M2c MΦ localized preferentially to the area of injury and kidney-draining lymph nodes, and their protective effect was associated with deactivation of endogenous renal MΦ and inhibition of CD4 T-cell proliferation. It appeared that M2c were more effective than M2a in reducing renal histological and functional injury with less proteinuria, tubular atrophy, intestinal volume expansion, and CD4 T-cell infiltration.15.Cao Q. Wang Y. Zheng D. et al.IL-10/TGFβ-modified macrophages induce regulatory T cells and protect against murine ariamycin nephrosis.J Am Soc Nephrol. 2010; 21: 933-942Crossref PubMed Scopus (200) Google Scholar,16.Lu J.Y. Cao Q. Zheng D. et al.Discrete functions of M and M macrophage subsets determine their relative efficacy in treating chronic kidney disease.Kidney Int. 2013; 84: 745-755Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar The greater potency of M2c than M2a could relate to the high-level expression of the regulatory co-stimulatory molecule B7-H4 on M2c that mediates Treg production.15.Cao Q. Wang Y. Zheng D. et al.IL-10/TGFβ-modified macrophages induce regulatory T cells and protect against murine ariamycin nephrosis.J Am Soc Nephrol. 2010; 21: 933-942Crossref PubMed Scopus (200) Google ScholarTable 1Protective effect of M2a and M2c in AN mice14.Wang Y. Wang Y.P. Zheng G. et al.Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease.Kidney Int. 2007; 72: 290-299Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar, 15.Cao Q. Wang Y. Zheng D. et al.IL-10/TGFβ-modified macrophages induce regulatory T cells and protect against murine ariamycin nephrosis.J Am Soc Nephrol. 2010; 21: 933-942Crossref PubMed Scopus (200) Google Scholar, 16.Lu J.Y. Cao Q. Zheng D. et al.Discrete functions of M and M macrophage subsets determine their relative efficacy in treating chronic kidney disease.Kidney Int. 2013; 84: 745-755Abstract Full Text Full Text PDF PubMed Scopus (150) Google ScholarM2aM2cCytokine expressionIL-10, TGF-βIL-10, TGF-βSurface moleculesMR, arginase, FIZZ-1MR, arginase, B7-H4Inhibit T-cell proliferation++Inhibit Mϕ activation++Induce Tregs-+Reduce renal injury+++Reduce renal fibrosis+++Abbreviations: AN, adriamycin nephropathy; IL, interleukin; MΦ, macrophage; TGF-β, transforming growth factor-beta; Tregs, regulatory T cells. Open table in a new tab Abbreviations: AN, adriamycin nephropathy; IL, interleukin; MΦ, macrophage; TGF-β, transforming growth factor-beta; Tregs, regulatory T cells. M2a MΦ have also been investigated in murine streptozotocin-induced diabetes.17.Zheng D. Wang Y. Cao Q. et al.Transfused macrophages ameliorate pancreatic and renal injury in murine diabetes mellitus.Nephron Exp Nephrol. 2011; 118: e87-e99Crossref PubMed Scopus (64) Google Scholar Transfused M2a MΦ accumulated progressively in kidneys for at least 10 weeks after streptozotocin and significantly reduced renal interstitial fibrosis and islet injury. Similarly, M2a MΦ transfusion of diabetic endothelial nitric oxide synthase knockout (eNOS-/-) mice resulted in less renal fibrosis and glomerulosclerosis than in untransfused diabetic eNOS-/- mice (unpublished data). M2 MΦ also can be induced in vivo. Our group found that interleukin (IL)-25, by increasing Th2 cell IL-4 and IL-13 production, induced M2 MΦ and attenuated kidney injury in AN mice, providing a possible strategy to induce M2 MΦ in vivo to limit renal inflammation.18.Cao Q. Wang C. Zheng D. et al.IL-25 induces M2 macrophages and reduces renal injury in proteinuric kidney disease.J Am Soc Nephrol. 2011; 22: 1229-1239Crossref PubMed Scopus (60) Google Scholar A large proportion of renal MΦ during inflammation and fibrosis originate from bone marrow (BM). We found that BM–derived MΦ have greater proliferative ability and less phenotypic stability in vitro than splenic (SP) and peritoneal MΦ.19.Wang C. Yu X. Cao Q. et al.Characterization of murine macrophages from bone marrow, spleen and peritoneum.BMC Immunol. 2013; 14: 6Crossref PubMed Scopus (130) Google Scholar Unlike SP-M2a, BM-M2a did not protect against renal structural or functional injury in murine AN. The failed renoprotection of BM-M2a was linked to their proliferation within inflamed kidney. BM-M2a MΦ, but not SP-M2a, proliferated strongly in kidney, and divided cells did not express the regulatory phenotype of M2. The likely explanation for the increased proliferation of BM-M2a, but not SP-M2a MΦ, was their increased expression of macrophage-colony–stimulating factor receptor in comparison with SP-M2a MΦ. Blockade of macrophage-colony–stimulating factor by a c-fms inhibitor not only limited BM-M2a MΦ proliferation, but also prevented phenotype shift. These data suggest that proliferation-dependent shift of phenotype could be limited by targeting macrophage-colony–stimulating factor.20.Cao Q. Wang Y. Zheng D. et al.Failed renoprotection by alternatively activated bone marrow macrophages is due to a proliferation-dependent phenotype switch in vivo.Kidney Int. 2014; 85: 794-806Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar MΦ display pro-inflammatory and anti-inflammatory phenotypes in vitro and in vitro. Our studies have demonstrated that they can be used as potential therapeutic tools to regulate inflammation and promote tissue repair in chronic kidney diseases. The antifibrotic effect of transfused M2 MΦ observed in AN mice could be explained by their production of anti-inflammatory cytokines and reduction of local inflammation, resulting in less renal injury and consequently less fibrosis. Traditionally, MΦ have been recognized as key factors that may promote renal fibrosis. However, several recent studies have suggested an antifibrotic role of infiltrating MΦ in obstructive nephropathy. Triggers of renal cell damage recruit circulating monocytes into interstitial compartments where they differentiate into M1 or M2 MΦ phenotypes depending on the local tissue environment. Interferon-related factor 4 and 5 have been found to be involved in macrophage activation.21.Satoh T. Takeuchi O. Vandenbon A. et al.The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection.Nat Immunol. 2010; 11: 936-944Crossref PubMed Scopus (847) Google Scholar,22.Krausgruber T. Blazek K. Smallie T. et al.IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses.Nat Immunol. 2011; 12: 231-238Crossref PubMed Scopus (859) Google Scholar Pro-inflammatory M1 MΦ release pro-inflammatory mediators including tumor necrosis factor-α and reactive oxygen species, which cause tissue inflammation and subsequent renal fibrosis. In contrast, anti-inflammatory M2 MΦ release anti-inflammatory mediators including IL-10 and transforming growth factor-beta; the latter suppresses renal inflammation yet promotes renal fibrosis.4.Ricardo S.D. van Goor H. Eddy A.A. Macrophage diversity in renal injury and repair.J Clin Invest. 2008; 118: 3522-3530Crossref PubMed Scopus (562) Google Scholar,5.Anders H.J. Ryu M. Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis.Kidney Int. 2011; 80: 915-925Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar,23.Cao Q. Wang Y. Harris D.C. Pathogenic and protective role of macrophages in kidney disease.Am J Physiol Renal Physiol. 2013; 305: F3-11Crossref PubMed Scopus (51) Google Scholar,24.Li M.O. Flavell R.A. Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10.Immunity. 2008; 28: 468-476Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar Systemic MΦ depletion 1 day before UUO resulted in reduced initial interstitial MΦ infiltration and also decreased renal fibrosis, suggesting that the initial phase of MΦ infiltration may promote subsequent renal fibrosis.25.Sung S.A. Jo S.K. Cho W.Y. et al.Reduction of renal fibrosis as a result of liposome encapsulated clodronate induced macrophage depletion after unilateral ureteral obstruction in rats.Nephron Exp Nephrol. 2007; 105: e1-e9Crossref PubMed Scopus (67) Google Scholar In the same way, administration of liposomal clodronate selectively depleted both F4/80+ MΦ and F4/80+ dendritic cells in mice with UUO, but not F4/80- dendritic cells, resulting in attenuated tubular apoptosis and renal fibrosis and decreased level of the profibrotic cytokine transforming growth factor-beta.26.Kitamoto K. Machida Y. Uchida J. et al.Effects of liposome clodronate on renal leukocyte populations and renal fibrosis in murine obstructive nephropathy.J Pharmacol Sci. 2009; 111: 285-292Crossref PubMed Scopus (110) Google Scholar Braga et al.27.Braga T.T. Correa-Costa M. Guise Y.F. et al.MyD88 signaling pathway is involved in renal fibrosis by favoring a TH2 immune response and activating alternative M2 macrophages.Mol Med. 2012; 18: 1231-1239Crossref PubMed Scopus (90) Google Scholar found that M2 MΦ contributed to renal fibrosis of UUO in a MyD88-dependent manner. Mediators released by injured tissue can activate infiltration MΦ through toll-like receptors and MyD88 signaling pathways, which promote renal fibrosis. These results suggest that targeting innate immune response signaling pathways of MΦ could be a possible therapeutic strategy against renal fibrosis. Our group found that matrix metalloprotease (MMP)-9 was involved in epithelial mesenchymal transition and thereby contributed to renal fibrosis.28.Zheng G. Lyons J.G. Tan T.K. et al.Disruption of E-cadherin by matrix metalloproteinase directly mediates epithelial-mesenchymal transition downstream of transforming growth factor-beta1 in renal tubular epithelial cells.Am J Pathol. 2009; 175: 580-591Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar, 29.Tan T.K. Zheng G. Hsu T.T. et al.Macrophage matrix metalloproteinase-9 mediates epithelial-mesenchymal transition in vitro in murine renal tubular cells.Am J Pathol. 2010; 176: 1256-1270Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 30.Tan T.K. Zheng G. Hsu T.T. et al.Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage.Lab Invest. 2013; 93: 434-449Crossref PubMed Scopus (103) Google Scholar Lipopolysaccharide/interferon-γ-activated M1 MΦ produced a large amount of MMP-9, which increased tubular cell epithelial mesenchymal transition via the beta-catenin pathway. Tubular epithelial cells were the predominant source of MMP-9 during the early stage of UUO, whereas tubular epithelial cells, MΦ, and myofibroblasts produced MMP-9 during late-stage UUO. Blockade of MMP-2/MMP-9 or MMP-9 alone significantly reduced tubular cell epithelial mesenchymal transition and renal fibrosis in UUO.30.Tan T.K. Zheng G. Hsu T.T. et al.Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage.Lab Invest. 2013; 93: 434-449Crossref PubMed Scopus (103) Google Scholar In contrast, an inverse correlation between the number of interstitial MΦ and the degree of fibrosis has been found recently in UUO, suggesting an antifibrotic role of infiltrating MΦ in the later recovery phase of obstructive nephropathy.8.Nishida M. Fujinaka H. Matsusaka T. et al.Absence of angiotensin II type 1 receptor in bone marrow-derived cells is detrimental in the evolution of renal fibrosis.J Clin Invest. 2002; 110: 1859-1868Crossref PubMed Scopus (119) Google Scholar,9.Lopez-Guisa J.M. Cai X. Collins S.J. et al.Mannose receptor 2 attenuates renal fibrosis.J Am Soc Nephrol. 2012; 23: 236-251Crossref PubMed Scopus (49) Google Scholar,31.Zhang G. Kim H. Cai X. et al.Urokinase receptor modulates cellular and angiogenic responses in obstructive nephropathy.J Am Soc Nephrol. 2003; 14: 1234-1253Crossref PubMed Scopus (53) Google Scholar, 32.Nishida M. Okumura Y. Fujimoto S. et al.Adoptive transfer of macrophages ameliorates renal fibrosis in mice.Biochem Biophys Res Commun. 2005; 332: 11-16Crossref PubMed Scopus (75) Google Scholar, 33.Nishida M. Okumura Y. Ozawa S. et al.MMP-2 inhibition reduces renal macrophage infiltration with increased fibrosis in UUO.Biochem Biophys Res Commun. 2007; 354: 133-139Crossref PubMed Scopus (47) Google Scholar Nishida et al.8.Nishida M. Fujinaka H. Matsusaka T. et al.Absence of angiotensin II type 1 receptor in bone marrow-derived cells is detrimental in the evolution of renal fibrosis.J Clin Invest. 2002; 110: 1859-1868Crossref PubMed Scopus (119) Google Scholar demonstrated that interstitial MΦ display an antifibrotic role at day 14, but not day 5 after UUO. They found that the angiotensin II type 1 receptor on MΦ functions to attenuate renal fibrosis in vivo. Their data suggest that angiotensin II affects the quantity and phagocytic activity of MΦ through the angiotensin II type 1 receptor. The inverse correlation between interstitial MΦ number and interstitial fibrosis at late stage (day 14) of UUO was confirmed using cyclophosphamide-mediated MΦ depletion.32.Nishida M. Okumura Y. Fujimoto S. et al.Adoptive transfer of macrophages ameliorates renal fibrosis in mice.Biochem Biophys Res Commun. 2005; 332: 11-16Crossref PubMed Scopus (75) Google Scholar Mannose receptor 2 (Mrc2) contains an extracellular fibronectin type II domain that binds to and internalizes collagen. Upregulated Mrc2 expression by MΦ and myofibroblasts has been shown in UUO, and reduced Mrc2 expression significantly worsened fibrosis in Mrc2-deficient mice. This study demonstrated a fibrosis-attenuating role of Mrc2-expressing MΦ, involving a lysosomal collagen turnover pathway.9.Lopez-Guisa J.M. Cai X. Collins S.J. et al.Mannose receptor 2 attenuates renal fibrosis.J Am Soc Nephrol. 2012; 23: 236-251Crossref PubMed Scopus (49) Google Scholar Zhang et al.31.Zhang G. Kim H. Cai X. et al.Urokinase receptor modulates cellular and angiogenic responses in obstructive nephropathy.J Am Soc Nephrol. 2003; 14: 1234-1253Crossref PubMed Scopus (53) Google Scholar showed that absence of scavenging receptors on uPAR-/- MΦ led to delayed clearance of profibrotic molecules, resulting in renal fibrosis in the late stage of the UUO model. Taken together, current data suggest a phase-dependent balance of profibrotic and antifibrotic effects of MΦ in UUO (Table 2). MΦ undergo a switch from a pro-inflammatory to a trophic phenotype that supports the transition from kidney injury to kidney repair. MΦ phenotypes depend on the influence of tissue microenvironments and are subject to change depending on the stage of disease, from early tissue injury to late wound repair. Renal fibrosis could be a consequence of renal injury, which involves MΦ infiltration. Inflammatory (M1) and anti-inflammatory (M2) MΦ will accelerate or reduce kidney injury, respectively, to impact indirectly on the degree of renal fibrosis (Figure 1). In contrast, MΦ at the later stage of repair may become profibrotic or fibrolytic to respectively induce or resolverenal fibrosis directly.5.Anders H.J. Ryu M. Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis.Kidney Int. 2011; 80: 915-925Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar However, existence of profibrotic and fibrolytic MΦ has yet to be demonstrated unequivocally in vivo CKD.Table 2Profibrotic and antifibrotic effects of macrophages in UUOMΦ phenotypeStage of UUOMediatorsCitationProfibroticEarly phase (days 1–7)Direct: TGF-β, MMP-9. Indirect: CCL2, TNF-α, ROS23.Cao Q. Wang Y. Harris D.C. Pathogenic and protective role of macrophages in kidney disease.Am J Physiol Renal Physiol. 2013; 305: F3-11Crossref PubMed Scopus (51) Google Scholar, 24.Li M.O. Flavell R.A. Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10.Immunity. 2008; 28: 468-476Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar, 25.Sung S.A. Jo S.K. Cho W.Y. et al.Reduction of renal fibrosis as a result of liposome encapsulated clodronate induced macrophage depletion after unilateral ureteral obstruction in rats.Nephron Exp Nephrol. 2007; 105: e1-e9Crossref PubMed Scopus (67) Google Scholar, 26.Kitamoto K. Machida Y. Uchida J. et al.Effects of liposome clodronate on renal leukocyte populations and renal fibrosis in murine obstructive nephropathy.J Pharmacol Sci. 2009; 111: 285-292Crossref PubMed Scopus (110) Google Scholar, 27.Braga T.T. Correa-Costa M. Guise Y.F. et al.MyD88 signaling pathway is involved in renal fibrosis by favoring a TH2 immune response and activating alternative M2 macrophages.Mol Med. 2012; 18: 1231-1239Crossref PubMed Scopus (90) Google Scholar, 28.Zheng G. Lyons J.G. Tan T.K. et al.Disruption of E-cadherin by matrix metalloproteinase directly mediates epithelial-mesenchymal transition downstream of transforming growth factor-beta1 in renal tubular epithelial cells.Am J Pathol. 2009; 175: 580-591Abstract Full Text Full Text PDF PubMed Scopus (198) Google ScholarAntifibroticLate phase (days 7–14)Direct: Agtr1, Mrc2, uPAR Indirect: IL-108.Nishida M. Fujinaka H. Matsusaka T. et al.Absence of angiotensin II type 1 receptor in bone marrow-derived cells is detrimental in the evolution of renal fibrosis.J Clin Invest. 2002; 110: 1859-1868Crossref PubMed Scopus (119) Google Scholar, 9.Lopez-Guisa J.M. Cai X. Collins S.J. et al.Mannose receptor 2 attenuates renal fibrosis.J Am Soc Nephrol. 2012; 23: 236-251Crossref PubMed Scopus (49) Google Scholar, 29.Tan T.K. Zheng G. Hsu T.T. et al.Macrophage matrix metalloproteinase-9 mediates epithelial-mesenchymal transition in vitro in murine renal tubular cells.Am J Pathol. 2010; 176: 1256-1270Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 30.Tan T.K. Zheng G. Hsu T.T. et al.Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage.Lab Invest. 2013; 93: 434-449Crossref PubMed Scopus (103) Google Scholar, 31.Zhang G. Kim H. Cai X. et al.Urokinase receptor modulates cellular and angiogenic responses in obstructive nephropathy.J Am Soc Nephrol. 2003; 14: 1234-1253Crossref PubMed Scopus (53) Google ScholarAbbreviations: Agtr1, angiotensin II type 1 receptor; CCL2, chemokine ligand 2; IL, interleukin; MΦ, macrophage; MMP, matrix metalloprotease; Mrc2, mannose receptor 2; ROS, reactive oxygen species; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha; uPAR, urokinase receptor; UUO, unilateral ureteral obstruction. Open table in a new tab Abbreviations: Agtr1, angiotensin II type 1 receptor; CCL2, chemokine ligand 2; IL, interleukin; MΦ, macrophage; MMP, matrix metalloprotease; Mrc2, mannose receptor 2; ROS, reactive oxygen species; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha; uPAR, urokinase receptor; UUO, unilateral ureteral obstruction. In summary, although classification of MΦ into M1 and M2 phenotypes is based primarily on in vitro studies and does not fully mirror MΦ phenotype in vivo, yet M1-like and M2-like MΦ have been demonstrated in kidney disease models. Functions of M1 and M2 MΦ have been demonstrated to be inflammatory and anti-inflammatory, respectively, which respond to and directly impact kidney injury. Modulation of MΦ ex vitro or in vivo into an anti-inflammatory phenotype presents a potential approach to limiting kidney injury by reducing inflammation. However, the exact phenotype and roles of MΦ in renal fibrosis are complex and uncertain. Profibrotic and fibrolytic MΦ have been defined in vitro, but their presence and function in vivo need to be verified in various types of kidney disease. This article is published in a supplement partially supported by the Major State Basic Research Development Program of China (no. 2012CB517700) and the Guangdong Medical Association. DCHH and YW have received grant support from the National Health and Medical Research Council (Australia).
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