Raf Kinase Inhibitor Protein RKIP Negatively Regulates Inflammasome Activation

Inflammasomes are a group of multimeric protein complexes comprised of an intracellular sensor,the precursor pro-caspase-1 and adaptor ASC in cells that regulate the activation of inflammatory caspase 1,inflammatory cytokines pro-IL-1? and the pro-IL-18,which are critical for inflammation and control of pathogen infection.At present,NLRP1,NLRP3,NLRC4 and AIM2 are better studied inflammasomes which are found to be closely related to many conditions such as inflammation,autoimmune diseases,metabolic syndrome and et al.Therefore,it's meaningful to investigate the underlying mechanism of inflammasome activation and to find an endogenous molecules which can be a target for future treatment.It has been reported that Raf kinase inhibitor protein RKIP regulates multiple signaling pathways,including Raf-1/MEK/ERK pathway,G Protein-Coupled Receptors transducing pathway and NF-kB pathway,to participate in cell growth,proliferation,differentiation and tumor deveopment.Here,we demonstrate that RKIP extensively inhibit the activation of NLRP1,NLRP3 and NLRC4 except for AIM2.Caspase 1 activated and IL-1?excreted are increased when RKIP-/-macrophages response to stimulators of NLRP3 inflammasome(ATP,Nigericin,Alum),NLRP1 inflammasome(MDP)and NLRC4 inflammasome(Flagellin)than wild type mice.RKIP deficiency enhances Alum induced peritonitis in mice.More neutrophils and monocytes are recruited to abdominal cavity and more IL-1? is excreted in RKIP-/-mice when compared to wild mice.Meanwhile,RKIP-/-mice are more sensitive to Salmonella typhimurium infection.Lower survival rate is observed and more IL-1? is excreted in abdominal cavity of RKIP-/-mice when compared to wild mice.We further found,RKIP bind to ASC and disturb the assembly and activation of NLRP3 inflammasome.Taken together,RKIP plays an important role in inflammasome activation and could potentially provide a new therapeutic target for treatment of diseases associated with inflammasome.