Netrin-1-treated macrophages protect the kidney against ischemia-reperfusion injury and suppress inflammation by inducing M2 polarization

Punithavathi Vilapakkam Ranganathan, Calpurnia Jayakumar, Ganesan Ramesh

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Improper macrophage activation is pathogenically linked to various metabolic, inflammatory, and immune disorders. Therefore, regulatory proteins controlling macrophage activation have emerged as important new therapeutic targets. We recently demonstrated that netrin-1 regulates inflammation and infiltration of monocytes and ameliorates ischemia-reperfusion-in-duced kidney injury. However, it was not known whether netrin-1 regulates the phenotype of macrophages and the signaling mechanism through which it might do this. In this study, we report novel mechanisms underlying netrin-1's effects on macrophages using in vivo and in vitro studies. Overexpression of netrin-1 in spleen and kidney of transgenic mice increased expression of arginase-1, IL-4, and IL-13 and decreased expression of COX-2, indicating a pheno-typic switch in macrophage polarization toward an M2-like phenotype. Moreover, flow cytometry analysis showed a significant increase in mannose receptor-positive macrophages in spleen compared with wild type. In vitro, netrin-1 induced the expression of M2 marker expression in bone marrow-derived macrophages, peritoneal macrophages, and RAW264.7 cells, and suppressed IFNγ-induced M1 polarization and production of inflammatory mediators. Adoptive transfer of netrin-1-treated macrophages suppressed inflammation and kidney injury against ischemia-reperfusion. Netrin-1 activated PPAR pathways and inhibition of PPAR activation abolished netrin-1-induced M2 polarization and suppression of cytokine production. Consistent with in vitro studies, administration of PPAR antagonist to mice abolished the netrin-1 protective effects against ischemia-reperfusion injury of the kidney. These findings illustrate that netrin-1 regulates macrophage polarization through PPAR pathways and confers anti-inflammatory actions in inflammed kidney tissue.

Original languageEnglish (US)
Pages (from-to)F948-F957
JournalAmerican Journal of Physiology - Renal Physiology
Volume304
Issue number7
DOIs
StatePublished - 2013

Keywords

  • Acute kidney injury
  • Ischemia-reperfusion injury
  • Macrophage polarization
  • Netrin-1
  • PPARγ

ASJC Scopus subject areas

  • Physiology
  • Urology

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