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Background  AKI is characterized by abrupt and reversible kidney dysfunction, and incomplete recovery leads to chronic kidney injury. Previous studies by us and others have indicated that macrophage infiltration and polarization play key roles in recovery from AKI. The role in AKI recovery played by IFN regulatory factor 4 (IRF4), a mediator of polarization of macrophages to the M2 phenotype, is unclear.    Methods  We used mice with myeloid or macrophage cell–specific deletion of  Irf4  (MΦ  Irf4   −/−  ) to evaluate Irf4’s role in renal macrophage polarization and development of fibrosis after severe AKI.    Results  Surprisingly, although macrophage  Irf4  deletion had a minimal effect on early renal functional recovery from AKI, it resulted in decreased renal fibrosis 4 weeks after severe AKI, in association with less-activated macrophages. Macrophage  Irf4  deletion also protected against renal fibrosis in unilateral ureteral obstruction. Bone marrow–derived monocytes (BMDMs) from MΦ  Irf4   −/−   mice had diminished chemotactic responses to macrophage chemoattractants, with decreased activation of AKT and PI3 kinase and increased PTEN expression. PI3K and AKT inhibitors markedly decreased chemotaxis in wild-type BMDMs, and in a cultured macrophage cell line. There was significant inhibition of homing of labeled  Irf4   −/−   BMDMs to postischemic kidneys. Renal macrophage infiltration in response to AKI was markedly decreased in MΦ  Irf4   −/−   mice or in wild-type mice with inhibition of AKT activity.    Conclusions  Deletion of  Irf4  from myeloid cells protected against development of tubulointerstitial fibrosis after severe ischemic renal injury in mice, due primarily to inhibition of AKT-mediated monocyte recruitment to the injured kidney and reduced activation and subsequent polarization into a profibrotic M2 phenotype.

journal of the american society of nephrology

Deletion of Myeloid Interferon Regulatory Factor 4 (Irf4) in Mouse Model Protects against Kidney Fibrosis after Ischemic Injury by Decreased Macrophage Recruitment and Activation