title: NLRP6 function in inflammatory monocytes reduces susceptibility to chemically induced intestinal injury.
abstract: NLRP6 is a member of the Nod-like receptor family, whose members are involved in the recognition of microbes and/or tissue injury. NLRP6 was previously demonstrated to regulate the production of interleukin (IL)-18 and is important for protecting mice against chemically induced intestinal injury and colitis-associated colon cancer. However, the cellular mechanisms by which NLRP6 reduces susceptibility to colonic inflammation remain unclear. Here, we determined that NLRP6 expression is specifically upregulated in Ly6Chiinflammatory monocytes that infiltrate into the colon during dextran sulfate sodium (DSS)-induced inflammation. Adoptive transfer of wild-type (WT) Ly6Chiinflammatory monocytes into Nlrp6-/-mice was sufficient to protect them from mortality, significantly reducing intestinal permeability and damage. NLRP6-deficient inflammatory monocytes were defective in tumor necrosis factor α (TNFα) production, which was important for reducing DSS-induced mortality and was dependent on autocrine IL-18 signaling by inflammatory monocytes. Our data reveal a previously unappreciated role for NLRP6 in inflammatory monocytes, which are recruited after DSS-induced intestinal injury to promote barrier function and limit bacteria-driven inflammation. This study highlights the importance of early cytokine responses, particularly NLRP6-dependent and IL-18-dependent TNFα production, in preventing chronic dysregulated inflammation.
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Seregin
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: N
authors.initials: N
authors.lastname: Golovchenko
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: B
authors.initials: B
authors.lastname: Schaf
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Eaton
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: G Y
authors.initials: GY
authors.lastname: Chen
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D016264:Dextran Sulfate; D004198:Disease Susceptibility; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D020382:Interleukin-18 / Q000378:metabolism*; D007422:Intestines / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology*; D009092:Mucous Membrane / Q000473:pathology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D020382:Interleukin-18; C494192:Ly-6C antigen, mouse; C559901:Nod-like receptor pyrin domain-containing protein 6, mouse; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate