Macrophage Phenotype Controls Long-Term AKI Outcomes—Kidney Regeneration versus Atrophy

• DOI: 10.1681/asn.2013020152
• Publication Date: 2013-12-06T02:38:40Z
• Authors: Maciej Lech; Regina Gröbmayr; Mi Ryu; Georg Lorenz; Ingo Hartter; Shrikant R. Mulay; Heni Eka Susanti; Koichi S. Kobayashi; Richard A. Flavell; Hans-Joachim Anders
• Keywords: Proinflammatory cytokine; Macrophage polarization

The mechanisms that determine full recovery versus subsequent progressive CKD after AKI are largely unknown. Because macrophages regulate inflammation as well epithelial recovery, we investigated whether macrophage activation influences outcomes. IL-1 receptor-associated kinase-M (IRAK-M) is a macrophage-specific inhibitor of Toll-like receptor (TLR) and signaling prevents polarization toward proinflammatory phenotype. In postischemic kidneys wild-type mice, IRAK-M expression increased for 3 weeks declined thereafter. However, genetic depletion did not affect immunopathology renal dysfunction during early AKI. Regarding long-term outcomes, regenerated completely within 5 contrast, IRAK-M(-/-) progressively lost up to two-thirds their original mass due tubule loss, leaving atubular glomeruli interstitial scarring. Moreover, M1 accumulated in the compartment, coincident with cytokines chemokines. Injection bacterial CpG DNA induced same effects TNF-α blockade etanercept partially prevented atrophy mice. These results suggest induction healing phase supports resolution macrophage- TNF-α-dependent inflammation, allowing structural regeneration functional injured kidney. Conversely, loss-of-function mutations or transient exposure may drive persistent inflammatory mononuclear phagocyte infiltrates, which impair kidney promote CKD. Overall, these support novel role regulation wound tissue regeneration.