Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Macrophages: versatile players in renal inflammation and fibrosis

Nature Reviews Nephrology volume 15, pages 144–158 (2019)Cite this article

Subjects

Abstract

Macrophages have important roles in immune surveillance and in the maintenance of kidney homeostasis; their response to renal injury varies enormously depending on the nature and duration of the insult. Macrophages can adopt a variety of phenotypes: at one extreme, M1 pro-inflammatory cells contribute to infection clearance but can also promote renal injury; at the other extreme, M2 anti-inflammatory cells have a reparative phenotype and can contribute to the resolution phase of the response to injury. In addition, bone marrow monocytes can differentiate into myeloid-derived suppressor cells that can regulate T cell immunity in the kidney. However, macrophages can also promote renal fibrosis, a major driver of progression to end-stage renal disease, and the CD206+ subset of M2 macrophages is strongly associated with renal fibrosis in both human and experimental diseases. Myofibroblasts are important contributors to renal fibrosis and recent studies provide evidence that macrophages recruited from the bone marrow can transition directly into myofibroblasts within the injured kidney. This process is termed macrophage-to-myofibroblast transition (MMT) and is driven by transforming growth factor-β1 (TGFβ1)–Smad3 signalling via a Src-centric regulatory network. MMT may serve as a key checkpoint for the progression of chronic inflammation into pathogenic fibrosis.

Key points

  • Macrophages have important roles in kidney homeostasis and in the response to acute and chronic kidney injury.

  • Macrophage phenotype varies enormously depending on the nature and duration of renal injury, ranging from the pro-inflammatory phenotype of M1 cells to the anti-inflammatory phenotype of M2 cells that are involved in tissue repair and fibrosis; monocytic myeloid-derived suppressor cells contribute to immune regulation.

  • Macrophages are plastic cells and their gene expression patterns and functions adapt rapidly to the dynamics of the renal microenvironment.

  • CD206+ M2 macrophages are strongly associated with renal fibrosis in human and experimental kidney diseases.

  • Macrophages derived from bone marrow cells can directly contribute to renal fibrosis through a process termed macrophage-to-myofibroblast transition (MMT).

  • The induction of MMT, via the Src-centric regulatory network mediated by transforming growth factor-β1 (TGFβ1)–Smad3, serves as a key checkpoint in the progression of chronic inflammation to renal fibrosis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Phenotype and function of bone-marrow-derived monocytes and macrophages in the injured kidney.
Fig. 2: Induction of M1 macrophages in renal inflammation.
Fig. 3: Regulation of the macrophage-to-myofibroblast transition.
Fig. 4: Duration of TGFβ1 signalling determines macrophage phenotype in renal repair and fibrosis.
Fig. 5: Potential therapeutic targets in macrophage-mediated renal injury.

Similar content being viewed by others

References

  1. Viehmann, S. F., Bohner, A. M. C., Kurts, C. & Brahler, S. The multifaceted role of the renal mononuclear phagocyte system. Cell. Immunol. 330, 97–104 (2018).

    CAS  PubMed  Google Scholar 

  2. MacPherson, G. G., Murphy, M. J. Jr & Morris, B. The traffic of mononuclear phagocytes through renal allografts in sheep. Transplantation 24, 16–28 (1977).

    CAS  PubMed  Google Scholar 

  3. Cline, M. J., Warner, N. L. & Metcalf, D. Identification of the bone marrow colony mononuclear phagocyte as a macrophage. Blood 39, 327–330 (1972).

    CAS  PubMed  Google Scholar 

  4. Muller, S. et al. Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment. Genome Biol. 18, 234 (2017).

    PubMed  PubMed Central  Google Scholar 

  5. Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Gabius, H. J. & Vehmeyer, K. Effect of microenvironment and cell-line type on carbohydrate-binding proteins of macrophage-like cells. Biochem. Cell Biol. 66, 1169–1176 (1988).

    CAS  PubMed  Google Scholar 

  7. Robertson, M. J. et al. Retinal microenvironment controls resident and infiltrating macrophage function during uveoretinitis. Invest. Ophthalmol. Vis. Sci. 43, 2250–2257 (2002).

    PubMed  Google Scholar 

  8. Weidenbusch, M. & Anders, H. J. Tissue microenvironments define and get reinforced by macrophage phenotypes in homeostasis or during inflammation, repair and fibrosis. J. Innate Immun. 4, 463–477 (2012).

    CAS  PubMed  Google Scholar 

  9. Knighton, D. R. & Fiegel, V. D. Macrophage-derived growth factors in wound healing: regulation of growth factor production by the oxygen microenvironment. Am. Rev. Respir. Dis. 140, 1108–1111 (1989).

    CAS  PubMed  Google Scholar 

  10. Das, A. et al. Monocyte and macrophage plasticity in tissue repair and regeneration. Am. J. Pathol. 185, 2596–2606 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Rosenberger, C. M. & Finlay, B. B. Phagocyte sabotage: disruption of macrophage signalling by bacterial pathogens. Nat. Rev. Mol. Cell Biol. 4, 385–396 (2003).

    CAS  PubMed  Google Scholar 

  12. Isbel, N. M. et al. Tubules are the major site of M-CSF production in experimental kidney disease: correlation with local macrophage proliferation. Kidney Int. 60, 614–625 (2001).

    CAS  PubMed  Google Scholar 

  13. Lever, J. M. et al. Parabiosis reveals leukocyte dynamics in the kidney. Lab. Invest. 98, 391–402 (2018).

    CAS  PubMed  Google Scholar 

  14. Gee, J. B., Hinman, L., Stevens, C. & Matthay, R. Human alveolar macrophage and obstructive lung disease. Chest 77, 271–272 (1980).

    CAS  PubMed  Google Scholar 

  15. Gendelman, H. E., Skillman, D. R. & Meltzer, M. S. Interferon alpha (IFN)-macrophage interactions in human immunodeficiency virus (HIV) infection: role of IFN in the tempo and progression of HIV disease. Int. Rev. Immunol. 8, 43–54 (1992).

    CAS  PubMed  Google Scholar 

  16. Li, H. et al. Cigarette smoke extract-treated mast cells promote alveolar macrophage infiltration and polarization in experimental chronic obstructive pulmonary disease. Inhal. Toxicol. 27, 822–831 (2015).

    PubMed  Google Scholar 

  17. Nikolic-Paterson, D. J., Wang, S. & Lan, H. Y. Macrophages promote renal fibrosis through direct and indirect mechanisms. Kidney Int. Suppl. 4, 34–38 (2014).

    CAS  Google Scholar 

  18. Sabelli, M. et al. Human macrophage ferroportin biology and the basis for the ferroportin disease. Hepatology 65, 1512–1525 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Brune, B., Weigert, A. & Dehne, N. Macrophage polarization in the tumor microenvironment. Redox Biol. 5, 419 (2015).

    PubMed  Google Scholar 

  20. Han, Y., Ma, F. Y., Tesch, G. H., Manthey, C. L. & Nikolic-Paterson, D. J. c-Fms blockade reverses glomerular macrophage infiltration and halts development of crescentic anti-GBM glomerulonephritis in the rat. Lab. Invest. 91, 978–991 (2011).

    CAS  PubMed  Google Scholar 

  21. Lech, M. et al. Macrophage phenotype controls long-term AKI outcomes—kidney regeneration versus atrophy. J. Am. Soc. Nephrol. 25, 292–304 (2014).

    CAS  PubMed  Google Scholar 

  22. Ma, F. Y. et al. TGF-beta1-activated kinase-1 regulates inflammation and fibrosis in the obstructed kidney. Am. J. Physiol. Renal Physiol. 300, F1410–F1421 (2011).

    CAS  PubMed  Google Scholar 

  23. Ma, R., Jiang, W., Li, Z., Sun, Y. & Wei, Z. Intrarenal macrophage infiltration induced by T cells is associated with podocyte injury in lupus nephritis patients. Lupus 25, 1577–1586 (2016).

    CAS  PubMed  Google Scholar 

  24. Tan, T. K. et al. Macrophage matrix metalloproteinase-9 mediates epithelial-mesenchymal transition in vitro in murine renal tubular cells. Am. J. Pathol. 176, 1256–1270 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Wise, A. F. et al. Human mesenchymal stem cells alter macrophage phenotype and promote regeneration via homing to the kidney following ischemia-reperfusion injury. Am. J. Physiol. Renal Physiol. 306, F1222–F1235 (2014).

    CAS  PubMed  Google Scholar 

  26. Zhang, X. L., Guo, Y. F., Song, Z. X. & Zhou, M. Vitamin D prevents podocyte injury via regulation of macrophage M1/M2 phenotype in diabetic nephropathy rats. Endocrinology 155, 4939–4950 (2014).

    PubMed  Google Scholar 

  27. Wang, S. et al. TGF-beta/Smad3 signalling regulates the transition of bone marrow-derived macrophages into myofibroblasts during tissue fibrosis. Oncotarget 7, 8809–8822 (2016).

    PubMed  Google Scholar 

  28. Wang, Y. Y. et al. Macrophage-to-myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury. J. Am. Soc. Nephrol. 28, 2053–2067 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Meng, X. M. et al. Inflammatory macrophages can transdifferentiate into myofibroblasts during renal fibrosis. Cell Death Dis. 7, e2495 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Gordon, S. & Pluddemann, A. Tissue macrophages: heterogeneity and functions. BMC Biol. 15, 53 (2017).

    PubMed  PubMed Central  Google Scholar 

  31. Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J. & Hill, A. M. M-1/M-2 macrophages and the Th1/Th2 paradigm. J. Immunol. 164, 6166–6173 (2000).

    CAS  PubMed  Google Scholar 

  32. Kiss, M., Van Gassen, S., Movahedi, K., Saeys, Y. & Laoui, D. Myeloid cell heterogeneity in cancer: not a single cell alike. Cell. Immunol. 330, 188–201 (2018).

    CAS  PubMed  Google Scholar 

  33. Cochain, C. et al. Single-cell RNA-seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ. Res. 122, 1661–1674 (2018).

    CAS  PubMed  Google Scholar 

  34. Kim, C. C., Nakamura, M. C. & Hsieh, C. L. Brain trauma elicits non-canonical macrophage activation states. J. Neuroinflammation 13, 117 (2016).

    PubMed  PubMed Central  Google Scholar 

  35. Puranik, A. S. et al. Kidney-resident macrophages promote a proangiogenic environment in the normal and chronically ischemic mouse kidney. Sci. Rep. 8, 13948 (2018).

    PubMed  PubMed Central  Google Scholar 

  36. Dai, X. et al. Acute Penicillium marneffei infection stimulates host M1/M2a macrophages polarization in BALB/C mice. BMC Microbiol. 17, 177 (2017).

    PubMed  PubMed Central  Google Scholar 

  37. Khan, J., Sharma, P. K. & Mukhopadhaya, A. Vibrio cholerae porin OmpU mediates M1-polarization of macrophages/monocytes via TLR1/TLR2 activation. Immunobiology 220, 1199–1209 (2015).

    CAS  PubMed  Google Scholar 

  38. Kalish, S. V. et al. Macrophages reprogrammed in vitro towards the M1 phenotype and activated with LPS extend lifespan of mice with Ehrlich ascites carcinoma. Med. Sci. Monit. Basic Res. 21, 226–234 (2015).

    PubMed  PubMed Central  Google Scholar 

  39. Murphy, B. S. et al. Azithromycin alters macrophage phenotype. J. Antimicrob. Chemother. 61, 554–560 (2008).

    CAS  PubMed  Google Scholar 

  40. Ishizuka, E. K. et al. Role of interplay between IL-4 and IFN-gamma in the in regulating M1 macrophage polarization induced by nattectin. Int. Immunopharmacol. 14, 513–522 (2012).

    CAS  PubMed  Google Scholar 

  41. Venturin, G. L., Chiku, V. M., Silva, K. L., de Almeida, B. F. & de Lima, V. M. M1 polarization and the effect of PGE2 on TNF-alpha production by lymph node cells from dogs with visceral leishmaniasis. Parasite Immunol. 38, 698–704 (2016).

    CAS  PubMed  Google Scholar 

  42. Wilson, H. M. et al. Inhibition of macrophage nuclear factor-kappaB leads to a dominant anti-inflammatory phenotype that attenuates glomerular inflammation in vivo. Am. J. Pathol. 167, 27–37 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Hennemann, B., Kreutz, M., Rehm, A. & Andreesen, R. Effect of granulocyte-macrophage colony-stimulating factor treatment on phenotype, cytokine release and cytotoxicity of circulating blood monocytes and monocyte-derived macrophages. Br. J. Haematol. 102, 1197–1203 (1998).

    CAS  PubMed  Google Scholar 

  44. Karuppagounder, V. et al. Curcumin alleviates renal dysfunction and suppresses inflammation by shifting from M1 to M2 macrophage polarization in daunorubicin induced nephrotoxicity in rats. Cytokine 84, 1–9 (2016).

    CAS  PubMed  Google Scholar 

  45. Lv, L. L. et al. The pattern recognition receptor, Mincle, is essential for maintaining the M1 macrophage phenotype in acute renal inflammation. Kidney Int. 91, 587–602 (2017).

    CAS  PubMed  Google Scholar 

  46. Iacopino, A. M. et al. Phenytoin and cyclosporine A specifically regulate macrophage phenotype and expression of platelet-derived growth factor and interleukin-1 in vitro and in vivo: possible molecular mechanism of drug-induced gingival hyperplasia. J. Periodontol. 68, 73–83 (1997).

    CAS  PubMed  Google Scholar 

  47. Onore, C. E. et al. Inflammatory macrophage phenotype in BTBR T+tf/J mice. Front. Neurosci. 7, 158 (2013).

    PubMed  PubMed Central  Google Scholar 

  48. Vinuesa, E. et al. Macrophage involvement in the kidney repair phase after ischaemia/reperfusion injury. J. Pathol. 214, 104–113 (2008).

    CAS  PubMed  Google Scholar 

  49. Huen, S. C. & Cantley, L. G. Macrophage-mediated injury and repair after ischemic kidney injury. Pediatr. Nephrol. 30, 199–209 (2015).

    PubMed  Google Scholar 

  50. Lee, S. et al. Distinct macrophage phenotypes contribute to kidney injury and repair. J. Am. Soc. Nephrol. 22, 317–326 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Alikhan, M. A. et al. Colony-stimulating factor-1 promotes kidney growth and repair via alteration of macrophage responses. Am. J. Pathol. 179, 1243–1256 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang, M. Z. et al. IL-4/IL-13-mediated polarization of renal macrophages/dendritic cells to an M2a phenotype is essential for recovery from acute kidney injury. Kidney Int. 91, 375–386 (2017).

    CAS  PubMed  Google Scholar 

  53. Cassol, E., Cassetta, L., Rizzi, C., Alfano, M. & Poli, G. M1 and M2a polarization of human monocyte-derived macrophages inhibits HIV-1 replication by distinct mechanisms. J. Immunol. 182, 6237–6246 (2009).

    CAS  PubMed  Google Scholar 

  54. Zhao, X. et al. PI3K/Akt signaling pathway modulates influenza virus induced mouse alveolar macrophage polarization to M1/M2b. PLOS ONE 9, e104506 (2014).

    PubMed  PubMed Central  Google Scholar 

  55. Lisi, L., Stigliano, E., Lauriola, L., Navarra, P. & Dello Russo, C. Proinflammatory-activated glioma cells induce a switch in microglial polarization and activation status, from a predominant M2b phenotype to a mixture of M1 and M2a/B polarized cells. ASN Neuro 6, 171–183 (2014).

    PubMed  Google Scholar 

  56. Kim, M. G. et al. The role of M2 macrophages in the progression of chronic kidney disease following acute kidney injury. PLOS ONE 10, e0143961 (2015).

    PubMed  PubMed Central  Google Scholar 

  57. Spiller, K. L. et al. The role of macrophage phenotype in vascularization of tissue engineering scaffolds. Biomaterials 35, 4477–4488 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Lu, J. et al. Discrete functions of M2a and M2c macrophage subsets determine their relative efficacy in treating chronic kidney disease. Kidney Int. 84, 745–755 (2013).

    CAS  PubMed  Google Scholar 

  59. Tang, L. et al. M2A and M2C macrophage subsets ameliorate inflammation and fibroproliferation in acute lung injury through interleukin 10 pathway. Shock 48, 119–129 (2017).

    CAS  PubMed  Google Scholar 

  60. Chaves, L. D. et al. Contrasting effects of systemic monocyte/macrophage and CD4+T cell depletion in a reversible ureteral obstruction mouse model of chronic kidney disease. Clin. Dev. Immunol. 2013, 836989 (2013).

    PubMed  PubMed Central  Google Scholar 

  61. Zhang, M. Z. et al. CSF-1 signaling mediates recovery from acute kidney injury. J. Clin. Invest. 122, 4519–4532 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Cao, Q. et al. Failed renoprotection by alternatively activated bone marrow macrophages is due to a proliferation-dependent phenotype switch in vivo. Kidney Int. 85, 794–806 (2014).

    CAS  PubMed  Google Scholar 

  63. Menezes, S. et al. The heterogeneity of Ly6C(hi) monocytes controls their differentiation into iNOS(+) macrophages or monocyte-derived dendritic cells. Immunity 45, 1205–1218 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Lin, S. L., Castano, A. P., Nowlin, B. T., Lupher, M. L. Jr & Duffield, J. S. Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations. J. Immunol. 183, 6733–6743 (2009).

    CAS  PubMed  Google Scholar 

  65. Rodero, M. P., Hodgson, S. S., Hollier, B., Combadiere, C. & Khosrotehrani, K. Reduced Il17a expression distinguishes a Ly6c(lo)MHCII(hi) macrophage population promoting wound healing. J. Invest. Dermatol. 133, 783–792 (2013).

    PubMed  Google Scholar 

  66. Clements, M. et al. Differential Ly6C expression after renal ischemia-reperfusion identifies unique macrophage populations. J. Am. Soc. Nephrol. 27, 159–170 (2016).

    CAS  PubMed  Google Scholar 

  67. Carlin, L. M. et al. Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal. Cell 153, 362–375 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Westhorpe, C. L. V. et al. Effector CD4(+) T cells recognize intravascular antigen presented by patrolling monocytes. Nat. Commun. 9, 747 (2018).

    PubMed  PubMed Central  Google Scholar 

  69. Ochando, J., Conde, P. & Bronte, V. Monocyte-derived suppressor cells in transplantation. Curr. Transplant. Rep. 2, 176–183 (2015).

    PubMed  PubMed Central  Google Scholar 

  70. Garcia, M. R. et al. Monocytic suppressive cells mediate cardiovascular transplantation tolerance in mice. J. Clin. Invest. 120, 2486–2496 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Yang, F. et al. TNFalpha-induced M-MDSCs promote transplant immune tolerance via nitric oxide. J. Mol. Med. 94, 911–920 (2016).

    CAS  PubMed  Google Scholar 

  72. Rogers, N. M., Ferenbach, D. A., Isenberg, J. S., Thomson, A. W. & Hughes, J. Dendritic cells and macrophages in the kidney: a spectrum of good and evil. Nat. Rev. Nephrol. 10, 625–643 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Gottschalk, C. & Kurts, C. The debate about dendritic cells and macrophages in the kidney. Front. Immunol. 6, 435 (2015).

    PubMed  PubMed Central  Google Scholar 

  74. Isbel, N. M., Nikolic-Paterson, D. J., Hill, P. A., Dowling, J. & Atkins, R. C. Local macrophage proliferation correlates with increased renal M-CSF expression in human glomerulonephritis. Nephrol. Dial. Transplant. 16, 1638–1647 (2001).

    CAS  PubMed  Google Scholar 

  75. Yang, N. et al. Local macrophage proliferation in human glomerulonephritis. Kidney Int. 54, 143–151 (1998).

    CAS  PubMed  Google Scholar 

  76. Nolasco, F. E. et al. Intraglomerular T cells and monocytes in nephritis: study with monoclonal antibodies. Kidney Int. 31, 1160–1166 (1987).

    CAS  PubMed  Google Scholar 

  77. Brasen, J. H. et al. Macrophage density in early surveillance biopsies predicts future renal transplant function. Kidney Int. 92, 479–489 (2017).

    PubMed  Google Scholar 

  78. Matturri, L., Ghidoni, P., Palazzi, P. & Stasi, P. Renal allograft rejection: immunohistochemistry of inflammatory cellular subsets and vascular lesions. Basic Appl. Histochem. 30, 267–277 (1986).

    CAS  PubMed  Google Scholar 

  79. Kashem, A. et al. Expression of inducible-NOS in human glomerulonephritis: the possible source is infiltrating monocytes/macrophages. Kidney Int. 50, 392–399 (1996).

    CAS  PubMed  Google Scholar 

  80. Noronha, I. L., Kruger, C., Andrassy, K., Ritz, E. & Waldherr, R. In situ production of TNF-alpha, IL-1 beta and IL-2R in ANCA-positive glomerulonephritis. Kidney Int. 43, 682–692 (1993).

    CAS  PubMed  Google Scholar 

  81. Wu, Q., Jinde, K., Endoh, M. & Sakai, H. Clinical significance of costimulatory molecules CD80/CD86 expression in IgA nephropathy. Kidney Int. 65, 888–896 (2004).

    CAS  PubMed  Google Scholar 

  82. D’Souza, M. J. et al. Macrophage depletion by albumin microencapsulated clodronate: attenuation of cytokine release in macrophage-dependent glomerulonephritis. Drug Dev. Ind. Pharm. 25, 591–596 (1999).

    PubMed  Google Scholar 

  83. Duffield, J. S. et al. Conditional ablation of macrophages halts progression of crescentic glomerulonephritis. Am. J. Pathol. 167, 1207–1219 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Ferenbach, D. A. et al. Macrophage/monocyte depletion by clodronate, but not diphtheria toxin, improves renal ischemia/reperfusion injury in mice. Kidney Int. 82, 928–933 (2012).

    CAS  PubMed  Google Scholar 

  85. Jo, S. K., Sung, S. A., Cho, W. Y., Go, K. J. & Kim, H. K. Macrophages contribute to the initiation of ischaemic acute renal failure in rats. Nephrol. Dial. Transplant. 21, 1231–1239 (2006).

    CAS  PubMed  Google Scholar 

  86. Jose, M. D., Ikezumi, Y., van Rooijen, N., Atkins, R. C. & Chadban, S. J. Macrophages act as effectors of tissue damage in acute renal allograft rejection. Transplantation 76, 1015–1022 (2003).

    CAS  PubMed  Google Scholar 

  87. Lan, H. Y., Nikolic-Paterson, D. J., Mu, W. & Atkins, R. C. Local macrophage proliferation in the progression of glomerular and tubulointerstitial injury in rat anti-GBM glomerulonephritis. Kidney Int. 48, 753–760 (1995).

    CAS  PubMed  Google Scholar 

  88. Jose, M. D., Le Meur, Y., Atkins, R. C. & Chadban, S. J. Blockade of macrophage colony-stimulating factor reduces macrophage proliferation and accumulation in renal allograft rejection. Am. J. Transplant. 3, 294–300 (2003).

    CAS  PubMed  Google Scholar 

  89. Le Meur, Y. et al. Macrophage accumulation at a site of renal inflammation is dependent on the M-CSF/c-fms pathway. J. Leukoc. Biol. 72, 530–537 (2002).

    PubMed  Google Scholar 

  90. Lim, A. K. et al. Antibody blockade of c-fms suppresses the progression of inflammation and injury in early diabetic nephropathy in obese db/db mice. Diabetologia 52, 1669–1679 (2009).

    CAS  PubMed  Google Scholar 

  91. Ma, F. Y., Woodman, N., Mulley, W. R., Kanellis, J. & Nikolic-Paterson, D. J. Macrophages contribute to cellular but not humoral mechanisms of acute rejection in rat renal allografts. Transplantation 96, 949–957 (2013).

    CAS  PubMed  Google Scholar 

  92. Tesch, G. H. MCP-1/CCL2: a new diagnostic marker and therapeutic target for progressive renal injury in diabetic nephropathy. Am. J. Physiol. Renal Physiol. 294, F697–F701 (2008).

    CAS  PubMed  Google Scholar 

  93. Lloyd, C. M. et al. RANTES and monocyte chemoattractant protein-1 (MCP-1) play an important role in the inflammatory phase of crescentic nephritis, but only MCP-1 is involved in crescent formation and interstitial fibrosis. J. Exp. Med. 185, 1371–1380 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Chow, F. Y. et al. Monocyte chemoattractant protein-1-induced tissue inflammation is critical for the development of renal injury but not type 2 diabetes in obese db/db mice. Diabetologia 50, 471–480 (2007).

    CAS  PubMed  Google Scholar 

  95. Chow, F. Y. et al. Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice. Kidney Int. 69, 73–80 (2006).

    CAS  PubMed  Google Scholar 

  96. Kang, Y. S. et al. CCR2 antagonism improves insulin resistance, lipid metabolism, and diabetic nephropathy in type 2 diabetic mice. Kidney Int. 78, 883–894 (2010).

    CAS  PubMed  Google Scholar 

  97. Haller, H., Bertram, A., Nadrowitz, F. & Menne, J. Monocyte chemoattractant protein-1 and the kidney. Curr. Opin. Nephrol. Hypertens. 25, 42–49 (2016).

    CAS  PubMed  Google Scholar 

  98. Li, L. et al. The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury. Kidney Int. 74, 1526–1537 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Peng, X., Zhang, J., Xiao, Z., Dong, Y. & Du, J. CX3CL1-CX3CR1 interaction increases the population of Ly6C(-)CX3CR1(hi) macrophages contributing to unilateral ureteral obstruction-induced fibrosis. J. Immunol. 195, 2797–2805 (2015).

    CAS  PubMed  Google Scholar 

  100. Zhuang, Q., Cheng, K. & Ming, Y. CX3CL1/CX3CR1 axis, as the therapeutic potential in renal diseases: friend or foe? Curr. Gene Ther. 17, 442–452 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Ma, Z., Jin, X., He, L. & Wang, Y. CXCL16 regulates renal injury and fibrosis in experimental renal artery stenosis. Am. J. Physiol. Heart Circ. Physiol. 311, H815–H821 (2016).

    PubMed  PubMed Central  Google Scholar 

  102. Lan, H. Y. et al. The pathogenic role of macrophage migration inhibitory factor in immunologically induced kidney disease in the rat. J. Exp. Med. 185, 1455–1465 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Lan, H. Y. et al. Expression of macrophage migration inhibitory factor in human glomerulonephritis. Kidney Int. 57, 499–509 (2000).

    CAS  PubMed  Google Scholar 

  104. Yu, X. Q. et al. A functional role for osteopontin in experimental crescentic glomerulonephritis in the rat. Proc. Assoc. Am. Physicians 110, 50–64 (1998).

    CAS  PubMed  Google Scholar 

  105. Tesch, G. H. Diabetic nephropathy — is this an immune disorder? Clin. Sci. 131, 2183–2199 (2017).

    CAS  PubMed  Google Scholar 

  106. Alexander, J. J., Chaves, L., Chang, A. & Quigg, R. J. The C5a receptor has a key role in immune complex glomerulonephritis in complement factor H-deficient mice. Kidney Int. 82, 961–968 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Lopez-Parra, V. et al. Fcgamma receptor deficiency attenuates diabetic nephropathy. J. Am. Soc. Nephrol. 23, 1518–1527 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Mocsai, A., Ruland, J. & Tybulewicz, V. L. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat. Rev. Immunol. 10, 387–402 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. McAdoo, S. P. et al. Correlation of disease activity in proliferative glomerulonephritis with glomerular spleen tyrosine kinase expression. Kidney Int. 88, 52–60 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Ryan, J. et al. Myeloid cell-mediated renal injury in rapidly progressive glomerulonephritis depends upon spleen tyrosine kinase. J. Pathol. 238, 10–20 (2016).

    CAS  PubMed  Google Scholar 

  111. Ryan, J., K., J., Blease, K., Ma, F. Y. & Nikolic-Paterson, D. J. Spleen tyrosine kinase signalling promotes myeloid cell recruitment and kidney damage following renal ischaemia/reperfusion injury. Am. J. Pathol. 186, 2032–2042 (2016).

    CAS  PubMed  Google Scholar 

  112. Ramessur Chandran, S. et al. Inhibition of spleen tyrosine kinase reduces renal allograft injury in a rat model of acute antibody-mediated rejection in sensitized recipients. Transplantation 101, e240–e248 (2017).

    CAS  PubMed  Google Scholar 

  113. Ma, F. Y., Blease, K. & Nikolic-Paterson, D. J. A role for spleen tyrosine kinase in renal fibrosis in the mouse obstructed kidney. Life Sci. 146, 192–200 (2016).

    CAS  PubMed  Google Scholar 

  114. Han, Y., Ma, F. Y., Di Paolo, J. & Nikolic-Paterson, D. J. An inhibitor of spleen tyrosine kinase suppresses experimental crescentic glomerulonephritis. Int. J. Immunopathol. Pharmacol. 32, 2058738418783404 (2018).

    PubMed  PubMed Central  Google Scholar 

  115. Awad, A. S. et al. Macrophage-derived tumor necrosis factor-alpha mediates diabetic renal injury. Kidney Int. 88, 722–733 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Lan, H. Y., Nikolic-Paterson, D. J., Zarama, M., Vannice, J. L. & Atkins, R. C. Suppression of experimental crescentic glomerulonephritis by the interleukin-1 receptor antagonist. Kidney Int. 43, 479–485 (1993).

    CAS  PubMed  Google Scholar 

  117. Lan, H. Y. et al. TNF-alpha up-regulates renal MIF expression in rat crescentic glomerulonephritis. Mol. Med. 3, 136–144 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Nikolic-Paterson, D. J., Lan, H. Y., Hill, P. A., Vannice, J. L. & Atkins, R. C. Suppression of experimental glomerulonephritis by the interleukin-1 receptor antagonist: inhibition of intercellular adhesion molecule-1 expression. J. Am. Soc. Nephrol. 4, 1695–1700 (1994).

    CAS  PubMed  Google Scholar 

  119. Timoshanko, J. R., Sedgwick, J. D., Holdsworth, S. R. & Tipping, P. G. Intrinsic renal cells are the major source of tumor necrosis factor contributing to renal injury in murine crescentic glomerulonephritis. J. Am. Soc. Nephrol. 14, 1785–1793 (2003).

    CAS  PubMed  Google Scholar 

  120. Ikezumi, Y., Atkins, R. C. & Nikolic-Paterson, D. J. Interferon-gamma augments acute macrophage-mediated renal injury via a glucocorticoid-sensitive mechanism. J. Am. Soc. Nephrol. 14, 888–898 (2003).

    CAS  PubMed  Google Scholar 

  121. Ikezumi, Y., Hurst, L., Atkins, R. C. & Nikolic-Paterson, D. J. Macrophage-mediated renal injury is dependent on signaling via the JNK pathway. J. Am. Soc. Nephrol. 15, 1775–1784 (2004).

    CAS  PubMed  Google Scholar 

  122. Schroder, K., Sweet, M. J. & Hume, D. A. Signal integration between IFNgamma and TLR signalling pathways in macrophages. Immunobiology 211, 511–524 (2006).

    CAS  PubMed  Google Scholar 

  123. Anders, H. J. et al. Activation of toll-like receptor-9 induces progression of renal disease in MRL-Fas(lpr) mice. FASEB J. 18, 534–536 (2004).

    CAS  PubMed  Google Scholar 

  124. Ryu, M. et al. Bacterial CpG-DNA accelerates Alport glomerulosclerosis by inducing an M1 macrophage phenotype and tumor necrosis factor-alpha-mediated podocyte loss. Kidney Int. 79, 189–198 (2011).

    CAS  PubMed  Google Scholar 

  125. Tomosugi, N. I. et al. Modulation of antibody-mediated glomerular injury in vivo by bacterial lipopolysaccharide, tumor necrosis factor, and IL-1. J. Immunol. 142, 3083–3090 (1989).

    CAS  PubMed  Google Scholar 

  126. Rosin, D. L. & Okusa, M. D. Dangers within: DAMP responses to damage and cell death in kidney disease. J. Am. Soc. Nephrol. 22, 416–425 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Komada, T. et al. Macrophage uptake of necrotic cell DNA activates the AIM2 inflammasome to regulate a proinflammatory phenotype in CKD. J. Am. Soc. Nephrol. 29, 1165–1181 (2018).

    CAS  PubMed  Google Scholar 

  128. Tian, S. et al. HMGB1 exacerbates renal tubulointerstitial fibrosis through facilitating M1 macrophage phenotype at the early stage of obstructive injury. Am. J. Physiol. Renal Physiol. 308, F69–F75 (2015).

    CAS  PubMed  Google Scholar 

  129. Wu, H. et al. HMGB1 contributes to kidney ischemia reperfusion injury. J. Am. Soc. Nephrol. 21, 1878–1890 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Chen, X. et al. Blockade of HMGB1 attenuates diabetic nephropathy in mice. Sci. Rep. 8, 8319 (2018).

    PubMed  PubMed Central  Google Scholar 

  131. Horiuchi, S. et al. Pathological roles of advanced glycation end product receptors SR-A and CD36. Ann. NY Acad. Sci. 1043, 671–675 (2005).

    CAS  PubMed  Google Scholar 

  132. Trial, J., Potempa, L. A. & Entman, M. L. The role of C-reactive protein in innate and acquired inflammation: new perspectives. Inflamm. Cell Signal. 3, e1409 (2016).

    PubMed  PubMed Central  Google Scholar 

  133. Li, Z. I. et al. C-Reactive protein promotes acute renal inflammation and fibrosis in unilateral ureteral obstructive nephropathy in mice. Lab. Invest. 91, 837–851 (2011).

    CAS  PubMed  Google Scholar 

  134. Liu, F. et al. C-Reactive protein promotes diabetic kidney disease in a mouse model of type 1 diabetes. Diabetologia 54, 2713–2723 (2011).

    CAS  PubMed  Google Scholar 

  135. You, Y. K. et al. C-reactive protein promotes diabetic kidney disease in db/db mice via the CD32b-Smad3-mTOR signaling pathway. Sci. Rep. 6, 26740 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Wang, Y. et al. Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease. Kidney Int. 72, 290–299 (2007).

    CAS  PubMed  Google Scholar 

  137. Tomita, N. et al. In vivo administration of a nuclear transcription factor-kappaB decoy suppresses experimental crescentic glomerulonephritis. J. Am. Soc. Nephrol. 11, 1244–1252 (2000).

    CAS  PubMed  Google Scholar 

  138. Bienvenu, L. A. et al. Macrophage mineralocorticoid receptor signaling plays a key role in aldosterone-independent cardiac fibrosis. Endocrinology 153, 3416–3425 (2012).

    CAS  PubMed  Google Scholar 

  139. Tesch, G. H. et al. Intrinsic renal cells are the major source of interleukin-1 beta synthesis in normal and diseased rat kidney. Nephrol. Dial. Transplant. 12, 1109–1115 (1997).

    CAS  PubMed  Google Scholar 

  140. Flanc, R. S. et al. A pathogenic role for JNK signaling in experimental anti-GBM glomerulonephritis. Kidney Int. 72, 698–708 (2007).

    CAS  PubMed  Google Scholar 

  141. Ma, F. Y. et al. Blockade of the c-Jun amino terminal kinase prevents crescent formation and halts established anti-GBM glomerulonephritis in the rat. Lab. Invest. 89, 470–484 (2009).

    CAS  PubMed  Google Scholar 

  142. Arnold, C. E. et al. A critical role for suppressor of cytokine signalling 3 in promoting M1 macrophage activation and function in vitro and in vivo. Immunology 141, 96–110 (2014).

    CAS  PubMed  Google Scholar 

  143. Martin-Fernandez, B. et al. Aldosterone induces renal fibrosis and inflammatory M1-macrophage subtype via mineralocorticoid receptor in rats. PLOS ONE 11, e0145946 (2016).

    PubMed  PubMed Central  Google Scholar 

  144. Huang, L. L. et al. Myeloid mineralocorticoid receptor activation contributes to progressive kidney disease. J. Am. Soc. Nephrol. 25, 2231–2240 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Bhatt, K. et al. Anti-inflammatory role of microRNA-146a in the pathogenesis of diabetic nephropathy. J. Am. Soc. Nephrol. 27, 2277–2288 (2016).

    CAS  PubMed  Google Scholar 

  146. Abraham, A. P., Ma, F. Y., Mulley, W. R., Nikolic-Paterson, D. J. & Tesch, G. H. Matrix metalloproteinase-12 deficiency attenuates experimental crescentic anti-glomerular basement membrane glomerulonephritis. Nephrology 23, 183–189 (2018).

    CAS  PubMed  Google Scholar 

  147. Kaneko, Y. et al. Macrophage metalloelastase as a major factor for glomerular injury in anti-glomerular basement membrane nephritis. J. Immunol. 170, 3377–3385 (2003).

    CAS  PubMed  Google Scholar 

  148. Moon, D. K. & Geczy, C. L. Recombinant IFN-gamma synergizes with lipopolysaccharide to induce macrophage membrane procoagulants. J. Immunol. 141, 1536–1542 (1988).

    CAS  PubMed  Google Scholar 

  149. Meng, X. M., Nikolic-Paterson, D. J. & Lan, H. Y. TGF-beta: the master regulator of fibrosis. Nat. Rev. Nephrol. 12, 325–338 (2016).

    CAS  PubMed  Google Scholar 

  150. Rockey, D. C., Bell, P. D. & Hill, J. A. Fibrosis—a common pathway to organ injury and failure. N. Engl. J. Med. 372, 1138–1149 (2015).

    CAS  PubMed  Google Scholar 

  151. Mackensen-Haen, S., Bader, R., Grund, K. E. & Bohle, A. Correlations between renal cortical interstitial fibrosis, atrophy of the proximal tubules and impairment of the glomerular filtration rate. Clin. Nephrol. 15, 167–171 (1981).

    CAS  PubMed  Google Scholar 

  152. Risdon, R. A., Sloper, J. C. & De Wardener, H. E. Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis. Lancet 2, 363–366 (1968).

    CAS  PubMed  Google Scholar 

  153. Danilewicz, M. & Wagrowska-Danielwicz, M. Morphometric and immunohistochemical insight into focal segmental glomerulosclerosis in obese and non-obese patients. Nefrologia 29, 35–41 (2009).

    CAS  PubMed  Google Scholar 

  154. Eardley, K. S. et al. The relationship between albuminuria, MCP-1/CCL2, and interstitial macrophages in chronic kidney disease. Kidney Int. 69, 1189–1197 (2006).

    CAS  PubMed  Google Scholar 

  155. Ikezumi, Y. et al. The sialoadhesin (CD169) expressing a macrophage subset in human proliferative glomerulonephritis. Nephrol. Dial. Transplant. 20, 2704–2713 (2005).

    CAS  PubMed  Google Scholar 

  156. Klessens, C. Q. F. et al. Macrophages in diabetic nephropathy in patients with type 2 diabetes. Nephrol. Dial. Transplant. 32, 1322–1329 (2017).

    CAS  PubMed  Google Scholar 

  157. Ikezumi, Y. et al. Contrasting effects of steroids and mizoribine on macrophage activation and glomerular lesions in rat thy-1 mesangial proliferative glomerulonephritis. Am. J. Nephrol. 31, 273–282 (2010).

    CAS  PubMed  Google Scholar 

  158. Ikezumi, Y. et al. Alternatively activated macrophages in the pathogenesis of chronic kidney allograft injury. Pediatr. Nephrol. 30, 1007–1017 (2015).

    PubMed  Google Scholar 

  159. Belliere, J. et al. Specific macrophage subtypes influence the progression of rhabdomyolysis-induced kidney injury. J. Am. Soc. Nephrol. 26, 1363–1377 (2015).

    CAS  PubMed  Google Scholar 

  160. Lin, L. & Hu, K. Tissue-type plasminogen activator modulates macrophage M2 to M1 phenotypic change through annexin A2-mediated NF-kappaB pathway. Oncotarget 8, 88094–88103 (2017).

    PubMed  PubMed Central  Google Scholar 

  161. Han, Y., Ma, F. Y., Tesch, G. H., Manthey, C. L. & Nikolic-Paterson, D. J. Role of macrophages in the fibrotic phase of rat crescentic glomerulonephritis. Am. J. Physiol. Renal Physiol. 304, F1043–F1053 (2013).

    CAS  PubMed  Google Scholar 

  162. Ikezumi, Y. et al. Identification of alternatively activated macrophages in new-onset paediatric and adult immunoglobulin A nephropathy: potential role in mesangial matrix expansion. Histopathology 58, 198–210 (2011).

    PubMed  Google Scholar 

  163. Toki, D. et al. The role of macrophages in the development of human renal allograft fibrosis in the first year after transplantation. Am. J. Transplant. 14, 2126–2136 (2014).

    CAS  PubMed  Google Scholar 

  164. Bellon, T. et al. Alternative activation of macrophages in human peritoneum: implications for peritoneal fibrosis. Nephrol. Dial. Transplant. 26, 2995–3005 (2011).

    CAS  PubMed  Google Scholar 

  165. Braga, T. T. et al. MyD88 signaling pathway is involved in renal fibrosis by favoring a TH2 immune response and activating alternative M2 macrophages. Mol. Med. 18, 1231–1239 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Kushiyama, T. et al. Alteration in the phenotype of macrophages in the repair of renal interstitial fibrosis in mice. Nephrology 16, 522–535 (2011).

    CAS  PubMed  Google Scholar 

  167. Yamate, J. et al. Participation of different macrophage populations and myofibroblastic cells in chronically developed renal interstitial fibrosis after cisplatin-induced renal injury in rats. Vet. Pathol. 39, 322–333 (2002).

    CAS  PubMed  Google Scholar 

  168. Shen, B., Liu, X., Fan, Y. & Qiu, J. Macrophages regulate renal fibrosis through modulating TGFbeta superfamily signaling. Inflammation 37, 2076–2084 (2014).

    CAS  PubMed  Google Scholar 

  169. Feng, Y. et al. Wnt/beta-catenin-promoted macrophage alternative activation contributes to kidney fibrosis. J. Am. Soc. Nephrol. 29, 182–193 (2018).

    CAS  PubMed  Google Scholar 

  170. Pennathur, S. et al. The macrophage phagocytic receptor CD36 promotes fibrogenic pathways on removal of apoptotic cells during chronic kidney injury. Am. J. Pathol. 185, 2232–2245 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Du, X. et al. Involvement of matrix metalloproteinase-2 in the development of renal interstitial fibrosis in mouse obstructive nephropathy. Lab. Invest. 92, 1149–1160 (2012).

    CAS  PubMed  Google Scholar 

  172. Eitner, F. et al. PDGF-C is a proinflammatory cytokine that mediates renal interstitial fibrosis. J. Am. Soc. Nephrol. 19, 281–289 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Henderson, N. C. et al. Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. Am. J. Pathol. 172, 288–298 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Jones, L. K. et al. IL-1RI deficiency ameliorates early experimental renal interstitial fibrosis. Nephrol. Dial. Transplant. 24, 3024–3032 (2009).

    CAS  PubMed  Google Scholar 

  175. Lan, H. Y., Nikolic-Paterson, D. J., Mu, W., Vannice, J. L. & Atkins, R. C. Interleukin-1 receptor antagonist halts the progression of established crescentic glomerulonephritis in the rat. Kidney Int. 47, 1303–1309 (1995).

    CAS  PubMed  Google Scholar 

  176. Niu, H. et al. Matrix metalloproteinase 12 modulates high-fat-diet induced glomerular fibrogenesis and inflammation in a mouse model of obesity. Sci. Rep. 6, 20171 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Tan, T. K. 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. 93, 434–449 (2013).

    CAS  PubMed  Google Scholar 

  178. Vesey, D. A., Cheung, C., Endre, Z., Gobe, G. & Johnson, D. W. Role of protein kinase C and oxidative stress in interleukin-1beta-induced human proximal tubule cell injury and fibrogenesis. Nephrology 10, 73–80 (2005).

    CAS  PubMed  Google Scholar 

  179. Barrera-Chimal, J. et al. The myeloid mineralocorticoid receptor controls inflammatory and fibrotic responses after renal injury via macrophage interleukin-4 receptor signaling. Kidney Int. 93, 1344–1355 (2018).

    CAS  PubMed  Google Scholar 

  180. Rickard, A. J. et al. Deletion of mineralocorticoid receptors from macrophages protects against deoxycorticosterone/salt-induced cardiac fibrosis and increased blood pressure. Hypertension 54, 537–543 (2009).

    CAS  PubMed  Google Scholar 

  181. Hochst, B. et al. Differential induction of Ly6G and Ly6C positive myeloid derived suppressor cells in chronic kidney and liver inflammation and fibrosis. PLOS ONE 10, e0119662 (2015).

    PubMed  PubMed Central  Google Scholar 

  182. Luan, Y. et al. Monocytic myeloid-derived suppressor cells accumulate in renal transplant patients and mediate CD4(+) Foxp3(+) Treg expansion. Am. J. Transplant. 13, 3123–3131 (2013).

    CAS  PubMed  Google Scholar 

  183. Lebrun, A. et al. CCR2(+) monocytic myeloid-derived suppressor cells (M-MDSCs) inhibit collagen degradation and promote lung fibrosis by producing transforming growth factor-beta1. J. Pathol. 243, 320–330 (2017).

    CAS  PubMed  Google Scholar 

  184. Bryant, A. J. et al. Myeloid-derived suppressor cells are necessary for development of pulmonary hypertension. Am. J. Respir. Cell. Mol. Biol. 58, 170–180 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Klingberg, F., Hinz, B. & White, E. S. The myofibroblast matrix: implications for tissue repair and fibrosis. J. Pathol. 229, 298–309 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Falke, L. L., Gholizadeh, S., Goldschmeding, R., Kok, R. J. & Nguyen, T. Q. Diverse origins of the myofibroblast-implications for kidney fibrosis. Nat. Rev. Nephrol. 11, 233–244 (2015).

    CAS  PubMed  Google Scholar 

  187. LeBleu, V. S. et al. Origin and function of myofibroblasts in kidney fibrosis. Nat. Med. 19, 1047–1053 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Qu, X. et al. Resolvins E1 and D1 inhibit interstitial fibrosis in the obstructed kidney via inhibition of local fibroblast proliferation. J. Pathol. 228, 506–519 (2012).

    CAS  PubMed  Google Scholar 

  189. Yang, N. et al. Local macrophage and myofibroblast proliferation in progressive renal injury in the rat remnant kidney. Nephrol. Dial. Transplant. 13, 1967–1974 (1998).

    CAS  PubMed  Google Scholar 

  190. Broekema, M. et al. Bone marrow-derived myofibroblasts contribute to the renal interstitial myofibroblast population and produce procollagen I after ischemia/reperfusion in rats. J. Am. Soc. Nephrol. 18, 165–175 (2007).

    CAS  PubMed  Google Scholar 

  191. Haudek, S. B. et al. Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice. Proc. Natl Acad. Sci. USA 103, 18284–18289 (2006).

    CAS  PubMed  Google Scholar 

  192. Jang, H. S., Kim, J. I., Han, S. J. & Park, K. M. Recruitment and subsequent proliferation of bone marrow-derived cells in the postischemic kidney are important to the progression of fibrosis. Am. J. Physiol. Renal Physiol. 306, F1451–F1461 (2014).

    CAS  PubMed  Google Scholar 

  193. Jang, H. S. et al. Bone marrow-derived cells play a major role in kidney fibrosis via proliferation and differentiation in the infiltrated site. Biochim. Biophys. Acta 1832, 817–825 (2013).

    CAS  PubMed  Google Scholar 

  194. Li, J., Deane, J. A., Campanale, N. V., Bertram, J. F. & Ricardo, S. D. The contribution of bone marrow-derived cells to the development of renal interstitial fibrosis. Stem Cells 25, 697–706 (2007).

    CAS  PubMed  Google Scholar 

  195. Phua, Y. L., Martel, N., Pennisi, D. J., Little, M. H. & Wilkinson, L. Distinct sites of renal fibrosis in Crim1 mutant mice arise from multiple cellular origins. J. Pathol. 229, 685–696 (2013).

    CAS  PubMed  Google Scholar 

  196. Grimm, P. C. et al. Neointimal and tubulointerstitial infiltration by recipient mesenchymal cells in chronic renal-allograft rejection. N. Engl. J. Med. 345, 93–97 (2001).

    CAS  PubMed  Google Scholar 

  197. Gomez, I. G. & Duffield, J. S. The FOXD1 lineage of kidney perivascular cells and myofibroblasts: functions and responses to injury. Kidney Int. Suppl. 4, 26–33 (2014).

    CAS  Google Scholar 

  198. Buchtler, S. et al. Cellular origin and functional relevance of collagen I production in the kidney. J. Am. Soc. Nephrol. 29, 1859–1873 (2018).

    CAS  PubMed  Google Scholar 

  199. Lin, S. L., Kisseleva, T., Brenner, D. A. & Duffield, J. S. Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am. J. Pathol. 173, 1617–1627 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Kramann, R. et al. Parabiosis and single-cell RNA sequencing reveal a limited contribution of monocytes to myofibroblasts in kidney fibrosis. JCI Insight 3, 99561 (2018).

    PubMed  Google Scholar 

  201. Bucala, R., Spiegel, L. A., Chesney, J., Hogan, M. & Cerami, A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol. Med. 1, 71–81 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Herzog, E. L. & Bucala, R. Fibrocytes in health and disease. Exp. Hematol. 38, 548–556 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Reich, B. et al. Fibrocytes develop outside the kidney but contribute to renal fibrosis in a mouse model. Kidney Int. 84, 78–89 (2013).

    CAS  PubMed  Google Scholar 

  204. Tang, P. M. et al. TGF-beta signalling in renal fibrosis: from Smads to non-coding RNAs. J. Physiol. 596, 3493–3503 (2018).

    CAS  PubMed  Google Scholar 

  205. Mezzano, S. A. et al. Overexpression of chemokines, fibrogenic cytokines, and myofibroblasts in human membranous nephropathy. Kidney Int. 57, 147–158 (2000).

    CAS  PubMed  Google Scholar 

  206. Chihara, Y. et al. Roles of TGF-beta1 and apoptosis in the progression of glomerulosclerosis in human IgA nephropathy. Clin. Nephrol. 65, 385–392 (2006).

    CAS  PubMed  Google Scholar 

  207. Brennan, E. P. et al. Next-generation sequencing identifies TGF-beta1-associated gene expression profiles in renal epithelial cells reiterated in human diabetic nephropathy. Biochim. Biophys. Acta 1822, 589–599 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Schena, F. P. & Gesualdo, L. Pathogenetic mechanisms of diabetic nephropathy. J. Am. Soc. Nephrol. 16, S30–S33 (2005).

    CAS  PubMed  Google Scholar 

  209. Meng, X. M., Tang, P. M., Li, J. & Lan, H. Y. Macrophage phenotype in kidney injury and repair. Kidney Dis. 1, 138–146 (2015).

    Google Scholar 

  210. Anders, H. J. & Ryu, M. Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis. Kidney Int. 80, 915–925 (2011).

    CAS  PubMed  Google Scholar 

  211. Gong, D. et al. TGFbeta signaling plays a critical role in promoting alternative macrophage activation. BMC  Immunol. 13, 31 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Sanjabi, S., Oh, S. A. & Li, M. O. Regulation of the immune response by TGF-beta: from conception to autoimmunity and infection. Cold Spring Harb. Perspect. Biol. 9, a022236 (2017).

    PubMed  Google Scholar 

  213. Shull, M. M. et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Fujimoto, M. et al. Mice lacking Smad3 are protected against streptozotocin-induced diabetic glomerulopathy. Biochem. Biophys. Res. Commun. 305, 1002–1007 (2003).

    CAS  PubMed  Google Scholar 

  215. Moon, J. A., Kim, H. T., Cho, I. S., Sheen, Y. Y. & Kim, D. K. IN-1130, a novel transforming growth factor-beta type I receptor kinase (ALK5) inhibitor, suppresses renal fibrosis in obstructive nephropathy. Kidney Int. 70, 1234–1243 (2006).

    CAS  PubMed  Google Scholar 

  216. Sato, M., Muragaki, Y., Saika, S., Roberts, A. B. & Ooshima, A. Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J. Clin. Invest. 112, 1486–1494 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Chen, J., Xia, Y., Lin, X., Feng, X. H. & Wang, Y. Smad3 signaling activates bone marrow-derived fibroblasts in renal fibrosis. Lab. Invest. 94, 545–556 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Mia, S., Warnecke, A., Zhang, X. M., Malmstrom, V. & Harris, R. A. An optimized protocol for human M2 macrophages using M-CSF and IL-4/IL-10/TGF-beta yields a dominant immunosuppressive phenotype. Scand. J. Immunol. 79, 305–314 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Zhang, F. et al. TGF-beta induces M2-like macrophage polarization via SNAIL-mediated suppression of a pro-inflammatory phenotype. Oncotarget 7, 52294–52306 (2016).

    PubMed  PubMed Central  Google Scholar 

  220. Guo, X. et al. Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR. Oncotarget 7, 80521–80542 (2016).

    PubMed  PubMed Central  Google Scholar 

  221. Saha, B., Kodys, K. & Szabo, G. Hepatitis C virus-induced monocyte differentiation into polarized M2 macrophages promotes stellate cell activation via TGF-beta. Cell. Mol. Gastroenterol. Hepatol. 2, 302–316 (2016).

    PubMed  PubMed Central  Google Scholar 

  222. Tang, P. M. et al. The proto-oncogene tyrosine protein kinase Src is essential for macrophage-myofibroblast transition during renal scarring. Kidney Int. 93, 173–187 (2018).

    CAS  PubMed  Google Scholar 

  223. Anguita, E. & Villalobo, A. Ca(2+) signaling and Src-kinases-controlled cellular functions. Arch. Biochem. Biophys. 650, 59–74 (2018).

    CAS  PubMed  Google Scholar 

  224. Skhirtladze, C. et al. Src kinases in systemic sclerosis: central roles in fibroblast activation and in skin fibrosis. Arthritis Rheum. 58, 1475–1484 (2008).

    CAS  PubMed  Google Scholar 

  225. Wang, J. & Zhuang, S. Src family kinases in chronic kidney disease. Am. J. Physiol. Renal Physiol. 313, F721–F728 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Yan, Y. et al. Src inhibition blocks renal interstitial fibroblast activation and ameliorates renal fibrosis. Kidney Int. 89, 68–81 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Chen, Y. et al. Src-mediated ligand release-independent EGFR transactivation involves TGF-beta-induced Smad3 activation in mesangial cells. Biochem. Biophys. Res. Commun. 493, 914–920 (2017).

    CAS  PubMed  Google Scholar 

  228. Wei, C. et al. Genomic analysis of kidney allograft injury identifies hematopoietic cell kinase as a key driver of renal fibrosis. J. Am. Soc. Nephrol. 28, 1385–1393 (2017).

    CAS  PubMed  Google Scholar 

  229. Gieseck, R. L. III, Wilson, M. S. & Wynn, T. A. Type 2 immunity in tissue repair and fibrosis. Nat. Rev. Immunol. 18, 62–76 (2018).

    CAS  PubMed  Google Scholar 

  230. Liu, L. et al. CD4+T Lymphocytes, especially Th2 cells, contribute to the progress of renal fibrosis. Am. J. Nephrol. 36, 386–396 (2012).

    CAS  PubMed  Google Scholar 

  231. Liang, H. et al. The IL-4 receptor alpha has a critical role in bone marrow-derived fibroblast activation and renal fibrosis. Kidney Int. 92, 1433–1443 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Yan, J., Zhang, Z., Yang, J., Mitch, W. E. & Wang, Y. JAK3/STAT6 stimulates bone marrow-derived fibroblast activation in renal fibrosis. J. Am. Soc. Nephrol. 26, 3060–3071 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. de Zeeuw, D. et al. The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial. Lancet Diabetes Endocrinol. 3, 687–696 (2015).

    PubMed  Google Scholar 

  234. Xia, Y., Entman, M. L. & Wang, Y. CCR2 regulates the uptake of bone marrow-derived fibroblasts in renal fibrosis. PLOS ONE 8, e77493 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Chen, G. et al. CXCL16 recruits bone marrow-derived fibroblast precursors in renal fibrosis. J. Am. Soc. Nephrol. 22, 1876–1886 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Sakai, N. et al. Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis. Proc. Natl Acad. Sci. USA 103, 14098–14103 (2006).

    CAS  PubMed  Google Scholar 

  237. Bahjat, F. R. et al. An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine lupus. Arthritis Rheum. 58, 1433–1444 (2008).

    CAS  PubMed  Google Scholar 

  238. McAdoo, S. P. et al. Spleen tyrosine kinase inhibition attenuates autoantibody production and reverses experimental autoimmune GN. J. Am. Soc. Nephrol. 25, 2291–2302 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Ma, T. K., McAdoo, S. P. & Tam, F. W. Spleen tyrosine kinase: a crucial player and potential therapeutic target in renal disease. Nephron 133, 261–269 (2016).

    CAS  PubMed  Google Scholar 

  240. Peyraud, F., Cousin, S. & Italiano, A. CSF-1R inhibitor development: current clinical status. Curr. Oncol. Rep. 19, 70 (2017).

    PubMed  Google Scholar 

  241. Kanellis, J. et al. JNK signalling in human and experimental renal ischaemia/reperfusion injury. Nephrol. Dial. Transplant. 25, 2898–2908 (2010).

    CAS  PubMed  Google Scholar 

  242. Ma, F. Y. et al. A pathogenic role for c-Jun amino-terminal kinase signaling in renal fibrosis and tubular cell apoptosis. J. Am. Soc. Nephrol. 18, 472–484 (2007).

    CAS  PubMed  Google Scholar 

  243. van der Velden, J. L. et al. JNK inhibition reduces lung remodeling and pulmonary fibrotic systemic markers. Clin. Transl Med. 5, 36 (2016).

    PubMed  PubMed Central  Google Scholar 

  244. Olgen, S. Design strategies, structures and molecular interactions of small molecule Src inhibitors. Anticancer Agents Med. Chem. 16, 992–1002 (2016).

    CAS  PubMed  Google Scholar 

  245. Berthier, C. C. et al. Enhanced expression of Janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy. Diabetes 58, 469–477 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  246. Brosius, F. C. III & He, J. C. JAK inhibition and progressive kidney disease. Curr. Opin. Nephrol. Hypertens. 24, 88–95 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  247. Tuttle, K. R. et al. JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a phase 2 randomized controlled clinical trial. Nephrol. Dial. Transplant. 33, 1950–1959 (2018).

    PubMed  PubMed Central  Google Scholar 

  248. Tan, K. C. B. et al. Galectin-3 is independently associated with progression of nephropathy in type 2 diabetes mellitus. Diabetologia 61, 1212–1219 (2018).

    CAS  PubMed  Google Scholar 

  249. Meng, X. M. et al. Treatment of renal fibrosis by rebalancing TGF-beta/Smad signaling with the combination of asiatic acid and naringenin. Oncotarget 6, 36984–36997 (2015).

    PubMed  PubMed Central  Google Scholar 

  250. Wu, H. et al. Single-cell transcriptomics of a human kidney allograft biopsy specimen defines a diverse inflammatory response. J. Am. Soc. Nephrol. 29, 2069–2080 (2018).

    CAS  PubMed  Google Scholar 

  251. Souma, T. et al. Plasticity of renal erythropoietin-producing cells governs fibrosis. J. Am. Soc. Nephrol. 24, 1599–1616 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  252. Zeisberg, E. M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat. Med. 13, 952–961 (2007).

    CAS  PubMed  Google Scholar 

  253. Zeisberg, E. M., Potenta, S. E., Sugimoto, H., Zeisberg, M. & Kalluri, R. Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J. Am. Soc. Nephrol. 19, 2282–2287 (2008).

    PubMed  PubMed Central  Google Scholar 

  254. Chen, Y. T. et al. Platelet-derived growth factor receptor signaling activates pericyte-myofibroblast transition in obstructive and post-ischemic kidney fibrosis. Kidney Int. 80, 1170–1181 (2011).

    CAS  PubMed  Google Scholar 

  255. Li, J., Qu, X. & Bertram, J. F. Endothelial-myofibroblast transition contributes to the early development of diabetic renal interstitial fibrosis in streptozotocin-induced diabetic mice. Am. J. Pathol. 175, 1380–1388 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. Iwano, M. et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest. 110, 341–350 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  257. Jinde, K. et al. Tubular phenotypic change in progressive tubulointerstitial fibrosis in human glomerulonephritis. Am. J. Kidney Dis. 38, 761–769 (2001).

    CAS  PubMed  Google Scholar 

  258. Ng, Y. Y. et al. Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats. Kidney Int. 54, 864–876 (1998).

    CAS  PubMed  Google Scholar 

  259. Anders, H. J. et al. The macrophage phenotype and inflammasome component NLRP3 contributes to nephrocalcinosis-related chronic kidney disease independent from IL-1-mediated tissue injury. Kidney Int. 93, 656–669 (2018).

    CAS  PubMed  Google Scholar 

  260. Fukasawa, M., Campeau, J. D., Yanagihara, D. L., Rodgers, K. E. & Dizerega, G. S. Mitogenic and protein synthetic activity of tissue repair cells: control by the postsurgical macrophage. J. Invest. Surg. 2, 169–180 (1989).

    CAS  PubMed  Google Scholar 

  261. Tamura, M., Aizawa, R., Hori, M. & Ozaki, H. Progressive renal dysfunction and macrophage infiltration in interstitial fibrosis in an adenine-induced tubulointerstitial nephritis mouse model. Histochem. Cell Biol. 131, 483–490 (2009).

    CAS  PubMed  Google Scholar 

  262. Pan, B., Liu, G., Jiang, Z. & Zheng, D. Regulation of renal fibrosis by macrophage polarization. Cell Physiol. Biochem. 35, 1062–1069 (2015).

    CAS  PubMed  Google Scholar 

  263. Quiroga, B., Arroyo, D. & de Arriba, G. Present and future in the treatment of diabetic kidney disease. J. Diabetes Res. 2015, 801348 (2015).

    PubMed  PubMed Central  Google Scholar 

  264. Saito, H. et al. Persistent expression of neutrophil gelatinase-associated lipocalin and M2 macrophage markers and chronic fibrosis after acute kidney injury. Physiol. Rep. 6, e13707 (2018).

    PubMed  PubMed Central  Google Scholar 

  265. Ma, T. K., McAdoo, S. P. & Tam, F. W. Targeting the tyrosine kinase signalling pathways for treatment of immune-mediated glomerulonephritis: from bench to bedside and beyond. Nephrol. Dial. Transplant. 32, i129–i138 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  266. Dai, X. Y. et al. Targeting c-fms kinase attenuates chronic aristolochic acid nephropathy in mice. Oncotarget 7, 10841–10856 (2016).

    PubMed  PubMed Central  Google Scholar 

  267. Grynberg, K., Ma, F. Y. & Nikolic-Paterson, D. J. The JNK signaling pathway in renal fibrosis. Front. Physiol. 8, 829 (2017).

    PubMed  PubMed Central  Google Scholar 

  268. Brosius, F. C., Tuttle, K. R. & Kretzler, M. JAK inhibition in the treatment of diabetic kidney disease. Diabetologia 59, 1624–1627 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  269. Perez-Gomez, M. V. et al. Horizon 2020 in diabetic kidney disease: the clinical trial pipeline for add-on therapies on top of renin angiotensin system blockade. J. Clin. Med. 4, 1325–1347 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors’ work is supported by grants from the Lui Che Woo Institute of Innovative Medicine (CARE programme), the Research Grants Council of Hong Kong (GRF 14106518, 14117418, 14117815, 14121816, 14163317, C7018-16G and TRS T12-402/13 N), the Health and Medical Research Fund (03140486 and 14152321), the Major State Basic Research Development Program of China (2012CB517705), a Direct Grant for Research from the Chinese University of Hong Kong (2017.002) and the National Health and Medical Research Council of Australia (1122073).

Reviewer information

Nature Reviews Nephrology thanks S. Ricardo, B. Conway and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Authors and Affiliations

  1. Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China

    Patrick Ming-Kuen Tang & Hui-Yao Lan

  2. Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China

    Patrick Ming-Kuen Tang

  3. Department of Nephrology, Monash Medical Centre and Monash University Centre for Inflammatory Diseases, Melbourne, Victoria, Australia

    David J. Nikolic-Paterson

Authors
  1. Patrick Ming-Kuen Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David J. Nikolic-Paterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hui-Yao Lan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

P.M.-K.T. and D.J.N.-P. drafted the manuscript. H.-Y.L. and D.J.N.-P. supervised the design, writing and content of the manuscript. All authors reviewed and/or edited the final version of the manuscript and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Hui-Yao Lan.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Clodronate liposomes

Phospholipid bilayers (that is, liposomes) that encapsulate the cytotoxic drug clodronate; these liposomes are used for the depletion of phagocytic cells as they are selectively taken up by phagocytes and cause cell death.

Fibrocytes

A population of immature myeloid cells in the bone marrow that differentiate into CD45+type I collagen+ fibroblast-like cells that are released into the circulation and can promote wound repair and tissue fibrosis.

Tumour-associated macrophages

A subset of macrophages in the tumour microenvironment that inhibit immune cell-mediated destruction of tumour cells and promote tumour growth via stimulation of angiogenesis.

Asiatic acid

A triterpenoid component extracted from Centella asiatica, which has anti-inflammatory and antifibrotic actions, including the increase in Smad7 expression.

Naringenin

A flavonoid from grapefruit and citrus fruits that has anti-inflammatory properties, including inhibition of Smad3 function.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tang, P.MK., Nikolic-Paterson, D.J. & Lan, HY. Macrophages: versatile players in renal inflammation and fibrosis. Nat Rev Nephrol 15, 144–158 (2019). https://doi.org/10.1038/s41581-019-0110-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41581-019-0110-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing