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.

Fig. 1

Regulation of canonical and noncanonical NF-κB signaling by negative regulatoryNucleotide-binding and leucine-rich repeat-containing receptors (NLRs). Activation of the NF-κB transcription factor occurs through canonical or noncanonical NF-κB signaling pathways. Negative regulatory NLRs, including NLRC3, NLRX1, and NLRP12, inhibit proper signal transduction of these pathways through protein interactions. NLRC3 and NLRX1 specifically dampen canonical NF-κB signaling by independently forming TRAFasome formations with TRAF6 to prevent its necessary auto-ubiquitination for further signal transduction. NLRP12 is demonstrated to inhibit canonical and noncanonical signaling. NLRP12 directly interacts with IRAK-1 to inhibiting its hyperphosphorylation and therefore preventing TLR2 and TLR4 signaling upstream of canonical NF-κB. NLRP12 also negatively regulates noncanonical NF-κB signaling in two manners: (1) by directly associating with NF-κB-inducing kinase (NIK) to promote its degradation or (2) by a TRAFasome formation between NIK and TRAF3 to promote degradation of NIK.