Distinct macrophage phenotypes contribute to kidney injury and repair

Sik Lee, Sarah Huen, Hitoshi Nishio, Saori Nishio, Heung Kyu Lee, Bum Soon Choi, Christiana Ruhrberg, Lloyd G. Cantley

Research output: Contribution to journalArticle

468 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)317-326
Number of pages10
JournalJournal of the American Society of Nephrology
Volume22
Issue number2
DOIs
StatePublished - Feb 2011

ASJC Scopus subject areas

  • Nephrology

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    Lee, S., Huen, S., Nishio, H., Nishio, S., Lee, H. K., Choi, B. S., Ruhrberg, C., & Cantley, L. G. (2011). Distinct macrophage phenotypes contribute to kidney injury and repair. Journal of the American Society of Nephrology, 22(2), 317-326. https://doi.org/10.1681/ASN.2009060615