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Novel Approach to Inhibit Asthma-Mediated Lung Inflammation Using Anti-CD147 Intervention¹

William M. Gwinn^*, Jesse M. Damsker^*, Rustom Falahati^*, Ifeanyi Okwumabua^*, Ann Kelly-Welch, Achsah D. Keegan, Christophe Vanpouille^*, James J. Lee, Lindsay A. Dent, David Leitenberg^*, Michael I. Bukrinsky^* and Stephanie L. Constant^2,*

^* Department of Microbiology, Immunology and Tropical Medicine, The George Washington University Medical Center, Washington, DC 20037; Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ 85259; and School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia

Extracellular cyclophilins have been well described as chemotactic factors for various leukocyte subsets. This chemotactic capacity is dependent upon interaction of cyclophilins with the cell surface signaling receptor CD147. Elevated levels of extracellular cyclophilins have been documented in several inflammatory diseases. We propose that extracellular cyclophilins, via interaction with CD147, may contribute to the recruitment of leukocytes from the periphery into tissues during inflammatory responses. In this study, we examined whether extracellular cyclophilin-CD147 interactions might influence leukocyte recruitment in the inflammatory disease allergic asthma. Using a mouse model of asthmatic inflammation, we show that 1) extracellular cyclophilins are elevated in the airways of asthmatic mice; 2) mouse eosinophils and CD4⁺ T cells express CD147, which is up-regulated on CD4⁺ T cells upon activation; 3) cyclophilins induce CD147-dependent chemotaxis of activated CD4⁺ T cells in vitro; 4) in vivo treatment with anti-CD147 mAb significantly reduces (by up to 50%) the accumulation of eosinophils and effector/memory CD4⁺ T lymphocytes, as well as Ag-specific Th2 cytokine secretion, in lung tissues; and 5) anti-CD147 treatment significantly reduces airway epithelial mucin production and bronchial hyperreactivity to methacholine challenge. These findings provide a novel mechanism whereby asthmatic lung inflammation may be reduced by targeting cyclophilin-CD147 interactions.

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 Grant R21-AI60730 (to S.L.C.).

² Address correspondence and reprint requests to Dr. Stephanie L. Constant, The George Washington University, Ross Hall 738, 2300 Eye Street, NW, Washington, DC 20037. E-mail address: mtmslc{at}gwumc.edu

³ Abbreviations used in this paper: AHR, airway hyperresponsiveness; Tg, transgenic; i.n., intranasal; BAL, bronchoalveolar lavage; CypA, cyclophilin A; CypB, cyclophilin B; PAS, periodic acid-Schiff; Penh, enhanced pause.

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