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Dipeptidyl Peptidase I-Dependent Neutrophil Recruitment Modulates the Inflammatory Response to Sendai Virus Infection¹

Antonina M. Akk^*, Pamela M. Simmons^*, Happy W. Chan^*, Eugene Agapov, Michael J. Holtzman^,, Mitchell H. Grayson and Christine T. N. Pham^2,*,¶

^* Division of Rheumatology, Division of Pulmonary and Critical Care Medicine, Division of Allergy and Immunology, Department of Internal Medicine, Department of Cell Biology, and ^¶ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

The role of innate immunity in the pathogenesis of asthma is unclear. Although increased presence of neutrophils is associated with persistent asthma and asthma exacerbations, how neutrophils participate in the pathogenesis of asthma remains controversial. In this study, we show that the absence of dipeptidyl peptidase I (DPPI), a lysosomal cysteine protease found in neutrophils, dampens the acute inflammatory response and the subsequent mucous cell metaplasia that accompanies the asthma phenotype induced by Sendai virus infection. This attenuated phenotype is accompanied by a significant decrease in the accumulation of neutrophils and the local production of CXCL2, TNF, IL-1β, and IL-6 in the lung of infected DPPI^–/– mice. Adoptive transfer of DPPI-sufficient neutrophils into DPPI^–/– mice restored the levels of CXCL2 and enhanced cytokine production on day 4 postinfection and subsequent mucous cell metaplasia on day 21 postinfection. These results indicate that DPPI and neutrophils play a critical role in Sendai virus-induced asthma phenotype as a result of a DPPI-dependent neutrophil recruitment and cytokine response.

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 from the Sandler Program for Asthma Research and the National Institutes of Health (National Institute of Allergy and Infectious Diseases and National Heart, Lung, and Blood Institute).

² Address correspondence and reprint requests to Dr. Christine T. N. Pham, 660 South Euclid Avenue, Box 8045, St. Louis, MO 63110. E-mail address: cpham{at}im.wustl.edu

³ Abbreviations used in this paper: CG, cathepsin G; BAL, bronchoalveolar lavage; DPPI, dipeptidyl peptidase I; LIX, LPS-induced CXC chemokine; NE, neutrophil elastase; PAS, periodic acid-Schiff; PI, postinfection; PR3, proteinase 3; SeV, Sendai virus; WT, wild type.