The inhibitor effect of RKIP on inflammasome activation and inflammasome-dependent diseases

Aberrant inflammasome activation contributes to the pathogenesis of various human diseases,including atherosclerosis,gout,and metabolic disorders.Elucidation of the underlying mechanism involved in the negative regulation of the inflammasome is important for developing new therapeutic targets for these diseases.Here,we showed that Raf kinase inhibitor protein(RKIP)negatively regulates the activation of the NLRP1,NLRP3,and NLRC4 inflammasomes.RKIP deficiency enhanced caspase-1 activation and IL-1P secretion via NLRP1,NLRP3,and NLRC4 Inflammasome activation In primary macrophages.The overexpression of RKIP in THP-1 cells inhibited NLRP1,NLRP3,and NLRC4 inflammasome activation.RKIP-deficient mice showed increased sensitivity to Aluminduced peritonitis and Salmonella typhimurium-induced inflammation,indicating that RKIP inhibits NLRP3 and NLRC4 inflammasome activation in vivo.Mechanistically,RKIP directly binds to apoptosis-associated speck-like protein containing a caspase-recruitment domain(ASC)and competes with NLRP1,NLRP3,or NLRC4 to interact with ASC thus interrupting inflammasome assembly and activation.The depletion of RKIP aggravated inflammasome-related diseases such as monosodium urate(MSU)-induced gouty arthritis and high-fat diet(HFD)-induced metabolic disorders.Furthermore,the expression of RKIP was substantially downregulated in patients with gouty arthritis or type 2 diabetes(T2D)compared to healthy controls.Collectively,our findings suggest that RKIP negatively regulates NLRP1,NLRP3,and NLRC4 inflammasome activation and is a potential therapeutic target for the treatment of inflammasome-related diseases.

Urothelial bladder cancer progression: lessons learned from the bench

Urothelial bladder carcinoma(UBC)is an intricate malignancy with a variable natural history and clinical behavior.Despite developments in diagnosis/prognosis refi nement and treatment modalities,the recurrence rate is high,and progression from non-muscle to muscle invasive UBC commonly leads to metastasis.Moreover,patients with muscle-invasive or extra-vesical disease often fail the standard chemotherapy treatment,and overall survival rates are poor.Thus,UBC remains a challenge in the oncology fi eld,representing an ideal candidate for research on biomarkers that could identify patients at increased risk of recurrence,progression,and chemo-refractoriness.However,progress toward personalized medicine has been hampered by the unique genetic complexity of UBC.Recent genome-wide expression and sequencing studies have brought new insights into its molecular features,pathogenesis and clinical diversity,revealing a landscape where classical pathology is intersected by the novel and heterogeneous molecular groups.Hence,it seems plausible to postulate that only an integrated signature of prognostic/predictive biomarkers inherent in different cancer hallmarks will reach clinical validation.In this review,we have summarized ours and others’research into novel putative biomarkers of progression and chemoresistance that encompass several hallmarks of cancer:tumor neovascularization,invasion and metastasis,and energy metabolism reprogramming of the tumor microenvironment.