title: Macrophage phenotype controls long-term AKI outcomes--kidney regeneration versus atrophy.
abstract: The mechanisms that determine full recovery versus subsequent progressive CKD after AKI are largely unknown. Because macrophages regulate inflammation as well as epithelial recovery, we investigated whether macrophage activation influences AKI outcomes. IL-1 receptor-associated kinase-M (IRAK-M) is a macrophage-specific inhibitor of Toll-like receptor (TLR) and IL-1 receptor signaling that prevents polarization toward a proinflammatory phenotype. In postischemic kidneys of wild-type mice, IRAK-M expression increased for 3 weeks after AKI and declined thereafter. However, genetic depletion of IRAK-M did not affect immunopathology and renal dysfunction during early postischemic AKI. Regarding long-term outcomes, wild-type kidneys regenerated completely within 5 weeks after AKI. In contrast, IRAK-M(-/-) kidneys progressively lost up to two-thirds of their original mass due to tubule loss, leaving atubular glomeruli and interstitial scarring. Moreover, M1 macrophages accumulated in the renal interstitial compartment, coincident with increased expression of proinflammatory cytokines and chemokines. Injection of bacterial CpG DNA induced the same effects in wild-type mice, and TNF-α blockade with etanercept partially prevented renal atrophy in IRAK-M(-/-) mice. These results suggest that IRAK-M induction during the healing phase of AKI supports the resolution of M1 macrophage- and TNF-α-dependent renal inflammation, allowing structural regeneration and functional recovery of the injured kidney. Conversely, IRAK-M loss-of-function mutations or transient exposure to bacterial DNA may drive persistent inflammatory mononuclear phagocyte infiltrates, which impair kidney regeneration and promote CKD. Overall, these results support a novel role for IRAK-M in the regulation of wound healing and tissue regeneration.
authors.affiliation: Division of Nephrology, Medical Clinic and Polyclinic IV, University of Munich, Munich, Germany;
authors.forename: Maciej
authors.initials: M
authors.lastname: Lech
authors.forename: Regina
authors.initials: R
authors.lastname: Gröbmayr
authors.forename: Mi
authors.initials: M
authors.lastname: Ryu
authors.forename: Georg
authors.initials: G
authors.lastname: Lorenz
authors.forename: Ingo
authors.initials: I
authors.lastname: Hartter
authors.forename: Shrikant R
authors.initials: SR
authors.lastname: Mulay
authors.forename: Heni Eka
authors.initials: HE
authors.lastname: Susanti
authors.forename: Koichi S
authors.initials: KS
authors.lastname: Kobayashi
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D058186:Acute Kidney Injury / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001284:Atrophy; D000068800:Etanercept; D005260:Female; D020869:Gene Expression Profiling; D007074:Immunoglobulin G / Q000494:pharmacology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007668:Kidney / Q000502:physiology; D007684:Kidney Tubules / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000145:classification / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D053573:Receptors, Interleukin-1 Type I / Q000037:antagonists & inhibitors; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors; D012038:Regeneration / Q000502:physiology*; D015427:Reperfusion Injury / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D051193:Toll-Like Receptors / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: C583355:IL1R1 protein, mouse; D007074:Immunoglobulin G; D053573:Receptors, Interleukin-1 Type I; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse; D000068800:Etanercept