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Nod1/RICK and TLR Signaling Regulate Chemokine and Antimicrobial Innate Immune Responses in Mesothelial Cells¹

Jong-Hwan Park^*, Yun-Gi Kim^*, Michael Shaw^*, Thirumala-Devi Kanneganti^*, Yukari Fujimoto, Koichi Fukase, Naohiro Inohara^* and Gabriel Núñez^2,*

^* Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109; Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan

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- and cooperated with IFN- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants DK61707 (to G.N.) and GM-60421 (to N.I.) from the National Institutes of Health. Y.-G.K. was supported by a fellowship from the University of Michigan Comprehensive Cancer Center.

² Address correspondence and reprint requests to Dr. Gabriel Núnez, Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109. E-mail address: bclx{at}umich.edu

³ Abbreviations used in this paper: Nod, nucleotide-binding oligomerization domain; NLR, Nod-like receptor; iNOS, inducible NO synthase; BMDM, bone marrow-derived macrophage; poly(I:C), polyinosinic-polycitidylic acid; meso-DAP, meso-diaminopimelic acid.

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