Negative regulatory NLRs mitigate inflammation via NF-κB pathway signaling in inflammatory bowel disease

Abstract

A subset of Nucleotide-binding and leucine-rich repeat-containing receptors (NLRs) function to mitigate overzealous pro-inflammatory signaling produced by NF-κB activation. Under normal pathophysiologic conditions, proper signaling by these NLRs protect against potential autoimmune responses. These NLRs associate with several different proteins within both the canonical and noncanonical NF-κB signaling pathways to either prevent activation of the pathway or inhibit signal transduction. Inhibition of the NF-κB pathways ultimately dampens the production of pro-inflammatory cytokines and activation of other downstream pro-inflammatory signaling mechanisms. Dysregulation of these NLRs, including NLRC3, NLRX1, and NLRP12, have been reported in human inflammatory bowel disease (IBD) and colorectal cancer patients, suggesting the potential of these NLRs as biomarkers for disease detection. Mouse models deficient in these NLRs also have increased susceptibility to colitis and colitis-associated colorectal cancer. While current standard of care for IBD patients and FDA-approved therapeutics function to remedy symptoms associated with IBD and chronic inflammation, these negative regulatory NLRs have yet to be explored as potential drug targets. In this review, we describe a comprehensive overview of recent studies that have evaluated the role of NLRC3, NLRX1, and NLRP12 in IBD and colitis-associated colorectal cancer.

Keywords: Colitis; Colorectal cancer; Dysbiosis; TRAF; TRAFasome.