J Immunol. 2026 Nov 2;215(11):vkag263. doi: 10.1093/jimmun/vkag263.
ABSTRACT
Nucleotide-binding, leucine-rich repeat-containing (NLR) innate immune proteins have been implicated in inflammatory bowel diseases (IBD). NLRC5 is a key trans-activator of class I MHC (MHC-I) genes, but it is also found to regulate cytokines and cell death. Meta-analysis of 14 different human RNAseq or microarray data (total n = 1,093) revealed a consistent and strong association between IBD and heightened NLRC5 expression, suggesting a role for NLRC5 across diverse IBD patients. Furthermore, these data show a strong correlation of NLRC5 with inflammation and STAT1 signatures, suggesting that its role in human IBD may extend beyond its canonical role as a regulator of MHC-I, or that its expression is controlled by inflammation/STAT1. However, in the dextran sulfate sodium (DSS)-induced colitis mouse model, Nlrc5 protected against colitis, which mimicked B2m-/- mice lacking MHC-I. This Nlrc5-associated protection has been consistent across hundreds of mice over a decade in the hands of several investigators. Microbiome study found significant alterations in the microbiota in overall composition and strain-specific differences over time, suggesting a dynamic relationship between microbiome dysbiosis and Nlrc5. To resolve these issues, we studied germ-free (GF) wild-type and Nlrc5-/- mice. Surprisingly, GF mice showed that Nlrc5 exacerbated instead of protected against DSS-induced colitis. A major difference between GF and conventionally-raised mice is that DSS reduced Nlrc5/ 2m expression in GF mice, while it did the opposite in SPF mice. These data highlight the complex role of Nlrc5 and the microbiome in the pathogenesis of IBD, as well as the necessity of complementary mouse models.
PMID:42995425 | DOI:10.1093/jimmun/vkag263