NLRP6 Negatively Regulates Innate Immunity and Host Defense Against Bacterial Pathogens

Members of the intracellular nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family contribute to immune responses through activation of NF-κB, type I interferon and inflammasome signaling(1). Mice lacking the NLR family member NLRP6 were recently shown to be susceptible to colitis and colorectal tumorigenesis(2-4), but the role of NLRP6 in microbial infections and the nature of the inflammatory signaling pathways regulated by NLRP6 remain unclear. Here, we show that Nlrp6-deficient mice were highly resistant to infection with the bacterial pathogens Listeria monocytogenes, Salmonella typhimurium and Escherichia coli. Infected Nlrp6-deficient mice had increased numbers of monocytes and neutrophils in circulation, and NLRP6 signaling in both hematopoietic and radio-resistant cells contributed to increased susceptibility. Nlrp6-deficiency enhanced activation of MAPK and canonical NF-κB upon TLR, but not cytosolic NOD1/2 ligation in vitro. Consequently, infected Nlrp6-deficient cells produced elevated levels of NF-κB- and MAPK-dependent cytokines and chemokines. Thus, our results reveal NLRP6 as a negative regulator of inflammatory signaling, and demonstrate a role for this NLR in impeding clearance of both Gram-positive and –negative bacterial pathogens.