title: NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens.
abstract: Members of the intracellular nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family contribute to immune responses through activation of nuclear factor-κB (NF-κB), type I interferon and inflammasome signalling. Mice lacking the NLR family member NLRP6 were recently shown to be susceptible to colitis and colorectal tumorigenesis, but the role of NLRP6 in microbial infections and the nature of the inflammatory signalling pathways regulated by NLRP6 remain unclear. Here we show that Nlrp6-deficient mice are 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 signalling in both haematopoietic and radioresistant cells contributed to increased susceptibility. Nlrp6 deficiency enhanced activation of mitogen-activated protein kinase (MAPK) and the canonical NF-κB pathway after Toll-like receptor ligation, but not cytosolic NOD1/2 ligation, in vitro. Consequently, infected Nlrp6-deficient cells produced increased levels of NF-κB- and MAPK-dependent cytokines and chemokines. Thus, our results reveal NLRP6 as a negative regulator of inflammatory signalling, and demonstrate a role for this NLR in impeding clearance of both Gram-positive and -negative bacterial pathogens.
authors: Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA.
authors: Paras K
authors: PK
authors: Anand
authors: R K Subbarao
authors: RK
authors: Malireddi
authors: John R
authors: JR
authors: Lukens
authors: Peter
authors: P
authors: Vogel
authors: John
authors: J
authors: Bertin
authors: Mohamed
authors: M
authors: Lamkanfi
authors: Thirumala-Devi
authors: TD
authors: Kanneganti
mesh_terms: D000818:Animals; D004198:Disease Susceptibility / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D007113:Immunity, Innate / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology*; D020935:MAP Kinase Signaling System; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000276:immunology*
chemical_list: D016328:NF-kappa B; C559901:Nod-like receptor pyrin domain-containing protein 6, mouse; D011956:Receptors, Cell Surface; D048049:Extracellular Signal-Regulated MAP Kinases