Emerging Role of LncRNA Regulation for NLRP3 Inflammasome in Diabetes Complications

Diabetes is a widespread metabolic disease with various complications, including diabetic nephropathy, retinopathy, cardiomyopathy, and other cardiovascular or cerebrovascular diseases. As the prevalence of diabetes increases in all age groups worldwide, diabetes and its complications cause an emerging public health burden. NLRP3 inflammasome is a complex of several proteins that play a critical role in inflammatory response and various diseases, including diabetes and its complications. Accumulating evidences indicate that NLRP3 inflammasome contributes to the development of diabetes and diabetic complications and that NLRP3 inflammation inactivation is beneficial in treating these illnesses. Emerging evidences suggest the critical role of long non-coding RNAs (lncRNAs) in regulating NLRP3 inflammasome activity in various diseases. LncRNAs are non-coding RNAs exceeding 200 nucleotides in length. Its dysregulation has been linked to the development of diseases, including diabetes. Recently, growing evidences hint that regulating lncRNAs on NLRP3 inflammasome is critical in developing and progressing diabetes and diabetic complications. Here, we discuss the role of lncRNAs in regulating NLRP3 inflammasome as well as its participation in diabetes and diabetic complications, providing novel insights into developing future therapeutic approaches for diabetes.

Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages

Candida albicans is the most common cause of fungal sepsis. Inhibition of inflammasome activity confers resistance to polymicrobial and LPS-induced sepsis; however, inflammasome signaling appears to protect against C. albicans infection, so inflammasome inhibitors are not clinically useful for candidiasis. Here we show disruption of GSDMD, a known inflammasome target and key pyroptotic cell death mediator, paradoxically alleviates candidiasis, improving outcomes and survival of Candida-infected mice. Mechanistically, C. albicans hijacked the canonical inflammasome-GSDMD axis-mediated pyroptosis to promote their escape from macrophages, deploying hyphae and candidalysin, a pore-forming toxin expressed by hyphae. GSDMD inhibition alleviated candidiasis by preventing C. albicans escape from macrophages while maintaining inflammasome-dependent but GSDMD-independent IL-1β production for anti-fungal host defenses. This study demonstrates key functions for GSDMD in Candida’s escape from host immunity in vitro and in vivo and suggests that GSDMD may be a potential therapeutic target in C. albicans-induced sepsis.

Spermidine reduces neuroinflammation and soluble amyloid beta in an Alzheimer's disease mouse model

Deposition of amyloid beta (A?) along with glia cell-mediated neuroinflammation are prominent pathogenic hallmarks of Alzheimer's disease (AD). In recent years, impairment of autophagy has been found to be another important feature, contributing to AD progression and aging. Therefore, we assessed the effect of the autophagy activator Spermidine, a small body-endogenous polyamine often used as dietary supplement and known to promote longevity, on glia cell-mediated neuroinflammation. Spermidine reduced TLR3- and TLR4-mediated inflammatory processes in microglia and astrocytes by decreasing cytotoxicity, inflammasome activity and NF-?B signaling. In line with these anti-inflammatory effects, oral treatment of the amyloid prone AD-like APPPS1 mice with Spermidine reduced neuroinflammation and neurotoxic soluble A?. Mechanistically, single nuclei sequencing revealed microglia as one of the main targets of Spermidine treatment, with increased expression of genes implicated in cell motility and phagocytosis. Thus, Spermidine provides a promising therapeutic potential to target glia cells in AD progression.

NLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly

NLRP3 controls the secretion of inflammatory cytokines IL-1β/18 and pyroptosis by assembling the inflammasome. Upon coordinated priming and activation stimuli, NLRP3 recruits NEK7 within hetero-oligomers that nucleate ASC and caspase-1 filaments, but the apical molecular mechanisms underlying inflammasome assembly remain elusive. Here we show that NEK7 recruitment to NLRP3 is controlled by the phosphorylation status of NLRP3 S803 located within the interaction surface, in which NLRP3 S803 is phosphorylated upon priming and later dephosphorylated upon activation. Phosphomimetic substitutions of S803 abolish NEK7 recruitment and inflammasome activity in macrophages in vitro and in vivo. In addition, NLRP3-NEK7 binding is also essential for NLRP3 deubiquitination by BRCC3 and subsequently inflammasome assembly, with NLRP3 phosphomimetic mutants showing enhanced ubiquitination and degradation than wildtype NLRP3. Finally, we identify CSNK1A1 as the kinase targeting NLRP3 S803. Our findings thus reveal NLRP3 S803 phosphorylation status as a druggable apical molecular mechanism controlling inflammasome assembly.