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Cutting Edge: Critical Role for Mesothelial Cells in Necrosis-Induced Inflammation through the Recognition of IL-1 Released from Dying Cells¹

Tatjana Eigenbrod^*, Jong-Hwan Park^*, Jürgen Harder^*, Yoichiro Iwakura and Gabriel Núñez^2,*

^* Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109; and Center for Medical Science, Institute of Medical Science, University of Tokyo, Tokyo, Japan

Endogenous danger signals released from necrotic cells are thought to be sensed by phagocytes leading to secretion of IL-1 and neutrophilic recruitment. However, the mechanisms for IL-1 production and IL-1-mediated sterile inflammation remain poorly understood. We report here that necrotic cell extracts elicited little secretion of CXCL1 and IL-6 from macrophages but robust production in mesothelial cells. The induction of CXCL1 as well as activation of NF-B and MAPKs by cytosolic extracts required the presence of IL-1 in the necrotic cell. Conversely, expression of IL-1R and MyD88 but not IL-1, RICK, TLR2, TLR4, TRIF, or inflammasome components in mesothelial cells was critical for the production of CXCL1. Furthermore, IL-1 was critical to induce the recruitment of neutrophils in the peritoneal cavity via CXCR2. These studies show that IL-1 is a key danger signal released from necrotic cells to trigger CXCL1 secretion and recruitment of neutrophils via IL-1R/MyD88 on neighboring 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 National Institutes of Health Grants AI063331 and AI064748 (to G.N.). T.E. was supported by a fellowship from the Jung-Stiftung für Wissenschaft und Forschung and by a fellowship from the German Research Foundation (Deutsche Forschungsgemeinschaft), and J. Harder was supported by a Heisenberg-Stipendium of the Deutsche Forschungsgemeinschaft.

² Address correspondence and reprint requests to Dr. Gabriel Núñez, Department of Pathology, University of Michigan Medical School, 4215 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48109. E-mail address: bclx{at}umich.edu

³ Abbreviations used in this paper: DC, dendritic cell; MC, mesothelial cell; WT, wild type.

⁴ The online version of this article contains supplemental material.

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