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 2/2 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-a blockade with etanercept partially prevented renal atrophy in IRAK-M 2/2 mice. These results suggest that IRAK-M induction during the healing phase of AKI supports the resolution of M1 macrophage-and TNF-a-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.

NLRP-3 inflammasome is one of several intracellular danger recognition platforms that integrates infectious or non-infectious types of danger into the expression of pro-inflammatory cytokines to set-up inflammation for danger control. NLRP3 activation induces three types of caspase-1-mediated responses: secretion of IL-1beta, secretion of IL-18 and a programmed form of cell death, referred to as pyroptosis. Similar to the well-documented impact of Toll-like receptor-driven danger signalling in kidney disease, evolving data now suggest a similar involvement of the NLRP3 inflammasome in renal inflammation. Here, we discuss the accumulating data on NLRP3 in the kidney: its IL-1beta and IL-18-dependent 'canonical' effects and the current evidence for its 'non-canonical' effects, e.g. in tumor growth factor (TGF)-beta signalling, epithelial-mesenchymal transition and fibrosis. Research in this area will certainly uncover yet unknown aspects of danger signalling in the kidney and how it drives renal inflammation and immunopathology.

Objectives The NLRP3/ASC inflammasome drives host defence and autoinflammatory disorders by activating caspase-1 to trigger the secretion of mature interleukin (IL)-1β/IL-18, but its potential role in autoimmunity is speculative. Methods We generated and phenotyped Nlrp3-deficient, Asc-deficient, Il-1r-deficient and Il-18-deficient C57BL/6-lpr/lpr mice, the latter being a mild model of spontaneous lupus-like autoimmunity.Results While lack of IL-1R or IL-18 did not affect the C57BL/6-lpr/lpr phenotype, lack of NLRP3 or ASC triggered massive lymphoproliferation, lung T cell infiltrates and severe proliferative lupus nephritis within 6 months, which were all absent in age-matched C57BL/ 6-lpr/lpr controls. Lack of NLRP3 or ASC increased dendritic cell and macrophage activation, the expression of numerous proinflammatory mediators, lymphocyte necrosis and the expansion of most T cell and B cell subsets. In contrast, plasma cells and autoantibody production were hardly affected. This unexpected immunosuppressive effect of NLRP3 and ASC may relate to their known role in SMAD2/3 phosphorylation during tumour growth factor (TGF)-β receptor signalling, for example, Nlrp3-deficiency and Asc-deficiency significantly suppressed the expression of numerous TGF-β target genes in C57BL/6-lpr/lpr mice and partially recapitulated the known autoimmune phenotype of Tgf-β1-deficient mice. Conclusions These data identify a novel non-canonical immunoregulatory function of NLRP3 and ASC in autoimmunity.