Vitamin D receptor enhances NLRC4 inflammasome activation by promoting NAIPs-NLRC4 association.

Inflammasomes are cytosolic multiprotein complexes that initiate host defense against bacterial pathogens. The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family caspase-associated recruitment domain-containing protein 4 (NLRC4) inflammasomes plays a critical role in the inflammatory response against intracellular bacterial infection. The NLR family apoptosis inhibitory proteins (NAIPs) detect Flagellin or type III secretion system (T3SS) microbial components to activate NLRC4 inflammasome. However, the underlying mechanism of NLRC4 inflammasome activation is not completely understood. Here, we show that the vitamin D receptor (VDR) is an essential immunological regulator of the NLRC4 inflammasome. Conditional VDR knockout mice (VDRflox/flox lyz2-Cre) exhibited impaired clearance of pathogens after acute Salmonella Typhimurium infection leading to poor survival. In macrophages, VDR deficiency reduced caspase-1 activation and IL-1ß secretion upon S. Typhimurium infection. For NAIPs act as upstream sensors for NLRC4 inflammasome assembly, the further study demonstrated that VDR promoted the NAIP-NLRC4 association and triggered NAIP-NLRC4 inflammasome activation, not NLRP3 activation. Moreover, Lys123 residue of VDR is identified as the critical amino acid for VDR-NLRC4 interaction, and the mutant VDR (K123A) effectively attenuates the NLRC4 inflammasome activation. Together, our findings suggest that VDR is a critical regulator of NAIPs-NLRC4 inflammasome activation, mediating innate immunity against bacterial infection.

Parkin increases the risk of colitis by downregulation of VDR via autophagy-lysosome degradation.

Parkin, an E3 ubiquitin ligase, plays an essential role in mitophagy. Emerging evidence indicates that mitophagy is involved in various processes closely related to immune diseases, including inflammatory bowel diseases (IBD). Here, the authors show that Parkin increases the occurrence of colitis and severe inflammation. Deletion of Parkin resulted in marked reductions in colonic inflammation and exhibited high resistance to DSS-induced colitis. Mechanism investigation indicated that Parkin interacts with Vitamin D receptors (VDR), a critical inhibitory regulator in IBD. Parkin promotes VDR degradation via the p62-related autophagy-lysosome pathway. Comparison of colitis in Parkin-/- and Parkin-/-Vdr-/- mice showed that the protective effect of Parkin deletion against colitis was abolished by VDR deletion. The result suggests that the regulatory effect of Parkin in colitis is a VDR-dependent pathway. Our research provides a new role of Parkin in colitis by downregulating VDR, which provides a potential strategy for treating IBD.