title: Nod1/RICK and TLR signaling regulate chemokine and antimicrobial innate immune responses in mesothelial cells.
abstract: Mesothelial cells that line the serous cavities and outer surface of internal organs are involved in inflammatory responses induced by microbial stimuli and bacterial infection. Upon exposure to bacterial products, mesothelial cells secrete chemokines, but the signaling pathways by which these cells recognize bacteria to mediate innate immune responses remain largely unknown. We report that stimulation of primary peritoneal mesothelial cells via nucleotide-binding oligomerization domain (Nod)1, a member of the intracytoplasmic Nod-like receptor family, induced potent secretion of the chemokines CXCL1 and CCL2 as well as expression of inducible NO synthase and such responses required the kinase RICK. Mesothelial cells also produced chemokines in response to TLR2, TLR3, TLR4, and TLR5 agonists, but unlike that induced by Nod1 stimulation, the TLR-mediated responses were independent of RICK. Yet, Nod1 stimulation of mesothelial cells via RICK enhanced chemokine secretion induced by LPS or IFN-gamma and cooperated with IFN-gamma in the production of NO. The i.p. administration of KF1B, a synthetic Nod1 agonist, elicited chemokine production in the serum and peritoneal fluid as well as the recruitment of neutrophils into the peritoneal cavity of wild-type mice, but not RICK-deficient mice. Finally, infection of mesothelial cells with Listeria monocytogenes induced production of CXCL1 and this response was significantly reduced in Nod1- or RICK-deficient cells. These results define mesothelial cells as microbial sensors through TLRs and Nod-like receptors and identify Nod1 and RICK as important mediators of chemokine and antimicrobial responses in mesothelial cells.
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
authors.forename: Jong-Hwan
authors.initials: JH
authors.lastname: Park
authors.forename: Yun-Gi
authors.initials: YG
authors.lastname: Kim
authors.forename: Michael
authors.initials: M
authors.lastname: Shaw
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
authors.forename: Yukari
authors.initials: Y
authors.lastname: Fujimoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukase
authors.forename: Naohiro
authors.initials: N
authors.lastname: Inohara
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
mesh_terms: D000818:Animals; D001202:Ascitic Fluid / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000378:metabolism; D054360:Chemokine CXCL1; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D007113:Immunity, Innate / Q000235:genetics; D007668:Kidney / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008099:Liver / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D053474:Nod1 Signaling Adaptor Protein / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051193:Toll-Like Receptors / Q000819:agonists / Q000502:physiology*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; D051193:Toll-Like Receptors; D052247:Nitric Oxide Synthase Type II; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2