NLRP12 regulates intestinal inflammation and tumorigenesis independent of gut microbiota

Abstract

Abstract Cytosolic NOD-like receptor NLRP12 plays a key role in suppressing intestinal inflammation and tumorigenesis via downregulation of NF-kB and MAPK pathways. Recent studies showed that altered gut microbiota in Nlrp12−/− mice is responsible for higher activation of NF-kB and MAPK pathways. Therefore, the precise function of NLRP12 in the intestinal remains poorly defined. Here we reinvestigated the contribution of gut microbiota in NLRP12-dependent regulation of colitis and colorectal cancer (CRC). We analyzed the microbiota composition of wild-type and Nlrp12−/− mice by 16S rRNA sequencing. Although there was a considerable difference in different microbial taxa between WT and Nlrp12−/− mice, no major difference was noted in Lachnospiraceae, which was previously been linked to hyperinflammatory responses in Nlrp12−/− mice. We next assessed the contribution of altered microbiota in colitis and CRC susceptibility of Nlrp12−/− mice. WT and Nlrp12−/− mice were co-housed before induction of experimental colitis and colorectal tumorigenesis. Separate or co-housed Nlrp12−/− mice developed significantly heightened colitis and increased burden of colorectal tumors. Higher activation of NF-kB, ERK, and STAT3 pathways was observed in both separate and co-housed Nlrp12−/− mouse colons during acute colitis. Further, macrophages from littermate or co-housed Nlrp12−/− mice exhibited hyperinflammatory responses along with higher activation of NF-kB and ERK pathways upon stimulation with LPS. Taken together, NLRP12 is an intrinsic regulator of NF-kB and MAPK pathways downstream of TLRs and suppresses inflammatory and tumorigenic responses in the intestine independent of gut microbiota.