Distinct macrophage phenotypes contribute to kidney injury and repair.

The ischemically injured kidney undergoes tubular cell necrosis and apoptosis, accompanied by an interstitial inflammatory cell infiltrate. In this study, we show that iNos-positive proinflammatory (M1) macrophages are recruited into the kidney in the first 48 hours after ischemia/reperfusion injury, whereas arginase 1- and mannose receptor-positive, noninflammatory (M2) macrophages predominate at later time points. Furthermore, depletion of macrophages before ischemia/reperfusion diminishes kidney injury, whereas depletion at 3 to 5 days after injury slows tubular cell proliferation and repair. Infusion of Ifnγ-stimulated, bone marrow-derived macrophages into macrophage-depleted mice at the time of kidney reperfusion restored injury to the level seen without macrophage depletion, suggesting that proinflammatory macrophages worsen kidney damage. In contrast, the appearance of macrophages with the M2 phenotype correlated with the proliferative phase of kidney repair. In vitro studies showed that IFNγ-stimulated, proinflammatory macrophages begin to express markers of M2 macrophages when cocultured with renal tubular cells. Moreover, IL-4-stimulated macrophages with an M2 phenotype, but not IFNγ-stimulated proinflammatory macrophages, promoted renal tubular cell proliferation. Finally, tracking fluorescently labeled, IFNγ-stimulated macrophages that were injected after injury showed that inflammatory macrophages can switch to an M2 phenotype in the kidney at the onset of kidney repair. Taken together, these studies show that macrophages undergo a switch from a proinflammatory to a trophic phenotype that supports the transition from tubule injury to tubule repair.

[1]  J. Moreira,et al.  Differential Macrophage Activation Alters the Expression Profile of NTPDase and Ecto-5′-Nucleotidase , 2012, PloS one.

[2]  J. Duffield Macrophages in kidney repair and regeneration. , 2011, Journal of the American Society of Nephrology : JASN.

[3]  Jie J. Zheng,et al.  Macrophage Wnt7b is critical for kidney repair and regeneration , 2010, Proceedings of the National Academy of Sciences.

[4]  A. Schwarting,et al.  CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice. , 2009, The Journal of clinical investigation.

[5]  S. Gordon,et al.  Alternative activation of macrophages: an immunologic functional perspective. , 2009, Annual review of immunology.

[6]  H. van Goor,et al.  Macrophage diversity in renal injury and repair. , 2008, The Journal of clinical investigation.

[7]  J. Torras,et al.  Macrophage involvement in the kidney repair phase after ischaemia/reperfusion injury , 2008, The Journal of pathology.

[8]  Y. Wang,et al.  Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease. , 2007, Kidney international.

[9]  K. Nath,et al.  Resident dendritic cells are the predominant TNF-secreting cell in early renal ischemia-reperfusion injury. , 2007, Kidney international.

[10]  Geert Raes,et al.  Classical and alternative activation of mononuclear phagocytes: picking the best of both worlds for tumor promotion. , 2006, Immunobiology.

[11]  M. Okusa,et al.  Blocking the immune response in ischemic acute kidney injury: the role of adenosine 2A agonists , 2006, Nature Clinical Practice Nephrology.

[12]  Hyoung-Kyu kim,et al.  Macrophages contribute to the initiation of ischaemic acute renal failure in rats. , 2006, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[13]  Cécile Chalouni,et al.  The intracellular domain of CD44 promotes the fusion of macrophages. , 2006, Blood.

[14]  H. Rabb,et al.  Role of the T-cell receptor in kidney ischemia-reperfusion injury. , 2006, Kidney international.

[15]  Liping Huang,et al.  Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: role of macrophages. , 2005, American journal of physiology. Renal physiology.

[16]  Silvano Sozzani,et al.  The chemokine system in diverse forms of macrophage activation and polarization. , 2004, Trends in immunology.

[17]  M. D. de Broe,et al.  T cells as mediators in renal ischemia/reperfusion injury. , 2004, Kidney international.

[18]  T. Wynn Fibrotic disease and the TH1/TH2 paradigm , 2004, Nature Reviews Immunology.

[19]  M. Wynes,et al.  Induction of Macrophage Insulin-Like Growth Factor-I Expression by the Th2 Cytokines IL-4 and IL-131 , 2003, The Journal of Immunology.

[20]  L. Cantley,et al.  Bone marrow stem cells contribute to repair of the ischemically injured renal tubule. , 2003, The Journal of clinical investigation.

[21]  W. Lieberthal,et al.  Chemical anoxia of tubular cells induces activation of c-Src and its translocation to the zonula adherens. , 2003, American journal of physiology. Renal physiology.

[22]  P. De Baetselier,et al.  Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages , 2002, Journal of leukocyte biology.

[23]  D. Remick,et al.  Neutralization of Groα and macrophage inflammatory protein-2 attenuates renal ischemia/reperfusion injury , 2001 .

[24]  L. Cantley,et al.  HGF promotes adhesion of ATP-depleted renal tubular epithelial cells in a MAPK-dependent manner. , 2001, American journal of physiology. Renal physiology.

[25]  R. Wüthrich,et al.  Hyaluronan induces monocyte chemoattractant protein-1 expression in renal tubular epithelial cells. , 1998, Journal of the American Society of Nephrology : JASN.

[26]  N. Van Rooijen,et al.  Effects of liposome-encapsulated drugs on macrophages: comparative activity of the diamidine 4',6-diamidino-2-phenylindole and the phenanthridinium salts ethidium bromide and propidium iodide. , 1998, Biochimica et biophysica acta.

[27]  F. Brombacher,et al.  Differences between IL-4Rα-deficient and IL-4-deficient mice reveal a role for IL-13 in the regulation of Th2 responses , 1998, Current Biology.

[28]  M. L. Watkins,et al.  A simplified method for isolation of large numbers of defined nephron segments. , 1997, American journal of physiology. Renal physiology.

[29]  W. Paul,et al.  An interleukin 4 (IL-4)-independent pathway for CD4+ T cell IL-4 production is revealed in IL-4 receptor-deficient mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Ya. S. Zukin,et al.  Immunohistochemical manifestations of unilateral kidney ischemia. , 1996, Clinical transplantation.

[31]  R. Colvin,et al.  Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. , 1996, The Journal of clinical investigation.

[32]  E. Neilson,et al.  Effects of cyclosporin A on the development of immune-mediated interstitial nephritis. , 1988, Kidney international.

[33]  K. Solez,et al.  The Morphology of “Acute Tubular Necrosis” in Man: Analysis of 57 Renal Biopsies and a Comparison with the Glycerol Model , 1979, Medicine.

[34]  Darmady Em,et al.  Acute tubular necrosis. , 1950, British medical journal.

[35]  J. Bonventre Pathophysiology of acute kidney injury: roles of potential inhibitors of inflammation. , 2007, Contributions to nephrology.

[36]  T. Wynn Fibrotic disease and the T(H)1/T(H)2 paradigm. , 2004, Nature reviews. Immunology.

[37]  D. Remick,et al.  Neutralization of Gro alpha and macrophage inflammatory protein-2 attenuates renal ischemia/reperfusion injury. , 2001, The American journal of pathology.