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CD44 Is a Negative Regulator of Acute Pulmonary Inflammation and Lipopolysaccharide-TLR Signaling in Mouse Macrophages¹

Jiurong Liang^*, Dianhua Jiang^*, Jason Griffith, Shuang Yu, Juan Fan, Xiaojian Zhao, Richard Bucala and Paul W. Noble^2,*

^* Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine, Durham, NC 27710; and Section of Rheumatology, Department of Medicine, and Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06520

CD44 is a transmembrane adhesion molecule and hemopoietic CD44 has an essential role in hyaluronan clearance and resolution of noninfectious lung injury. In this study, we examined the role of CD44 in acute pulmonary inflammation and in the regulation of LPS-TLR signaling. Following intratracheally LPS treatment, CD44^–/– mice demonstrated an exaggerated inflammatory response characterized by increased inflammatory cell recruitment, elevated chemokine expression in bronchoalveolar lavage fluid, and a marked increase in NF-B DNA-binding activity in lung tissue in vivo and in macrophages in vitro. Furthermore, CD44^–/– mice were more susceptible to LPS-induced shock. Reconstitution of hemopoietic CD44 reversed the inflammatory phenotype. We further found that the induction of the negative regulators of TLR signaling IL-1R-associated kinase-M, Toll-interacting protein, and A20 by intratracheal LPS in vivo and in macrophages in vitro was significantly reduced in CD44^–/– mice. Collectively, these data suggest CD44 plays a previously unrecognized role in preventing exaggerated inflammatory responses to LPS by promoting the expression of negative regulators of TLR-4 signaling.

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 HL57486 and AI52487 (to P.W.N.).

² Address correspondence and reprint requests to Dr. Paul W. Noble, Department of Medicine Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University School of Medicine, Durham, NC 27710. E-mail address: paul.noble{at}duke.edu

³ Abbreviations used in this paper: IRAK-M, IL-1R-associated kinase M; Tollip, Toll-interacting protein; SOCS, suppressor of cytokine signaling; BAL, bronchoalveolar lavage; bHABP, biotinylated hyaluronan-binding protein; PMN, polymorphonuclear neutrophil; HA, hyaluronan.

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