title: Salmonella exploits NLRP12-dependent innate immune signaling to suppress host defenses during infection.
abstract: The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 12 (NLRP12) plays a protective role in intestinal inflammation and carcinogenesis, but the physiological function of this NLR during microbial infection is largely unexplored. Salmonella enterica serovar Typhimurium (S. typhimurium) is a leading cause of food poisoning worldwide. Here, we show that NLRP12-deficient mice were highly resistant to S. typhimurium infection. Salmonella-infected macrophages induced NLRP12-dependent inhibition of NF-κB and ERK activation by suppressing phosphorylation of IκBα and ERK. NLRP12-mediated down-regulation of proinflammatory and antimicrobial molecules prevented efficient clearance of bacterial burden, highlighting a role for NLRP12 as a negative regulator of innate immune signaling during salmonellosis. These results underscore a signaling pathway defined by NLRP12-mediated dampening of host immune defenses that could be exploited by S. typhimurium to persist and survive in the host.
authors.affiliation: Department of Immunology and Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Md Hasan
authors.initials: MH
authors.lastname: Zaki
authors.forename: Si Ming
authors.initials: SM
authors.lastname: Man
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.forename: Mohamed
authors.initials: M
authors.lastname: Lamkanfi
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000382:microbiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D007249:Inflammation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000382:microbiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry; D009711:Nucleotides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D012481:Salmonella Infections, Animal / Q000276:immunology* / Q000382:microbiology*; D012486:Salmonella typhimurium / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C553199:NLRP12 protein, mouse; D009711:Nucleotides; D009569:Nitric Oxide; D048049:Extracellular Signal-Regulated MAP Kinases