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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901316v1 183/3/1964    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Szymczak, W. A. Articles by Deepe, G. S. PubMed PubMed Citation Articles by Szymczak, W. A. Articles by Deepe, G. S., Jr

The CCL7-CCL2-CCR2 Axis Regulates IL-4 Production in Lungs and Fungal Immunity¹

Wendy A. Szymczak^*, and George S. Deepe, Jr^2,*,

^* Division of Infectious Diseases, University of Cincinnati, Cincinnati, OH 45267; Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267; and Division of Infectious Diseases, Veterans Affairs Hospital, Cincinnati, OH 45267

Expression of the chemokine receptor CCR2 can be detrimental or beneficial for infection resolution. Herein, we examined whether CCR2 was requisite for control of infection by the dimorphic fungus Histoplasma capsulatum. H. capsulatum-infected CCR2^–/– mice manifested defects in inflammatory cell recruitment, increased IL-4, and progressive infection. Increased IL-4 in CCR2^–/– mice primarily contributed to decreased host resistance as demonstrated by the ability of IL-4-neutralized CCR2^–/– mice to resolve infection without altering inflammatory cell recruitment. Surprisingly, numerous alveolar macrophages and dendritic cells contributed to IL-4 production in CCR2^–/– mice. IL-4-mediated impairment of immunity in CCR2^–/– mice was associated with increased arginase-1 and YM1 transcription and increased transferrin receptor expression by phagocytic cells. Immunity in mice lacking the CCR2 ligand CCL2 was not impaired despite decreased inflammatory cell recruitment. Neutralization of the CCR2 ligand CCL7 in CCL2^–/– mice, but not wild type, resulted in increased IL-4 and fungal burden. Thus, CCL7 in combination with CCL2 limits IL-4 generation and exerts control of host resistance. Furthermore, increased phagocyte-derived IL-4 in CCR2^–/– mice is associated with the presence of alternatively activated phagocytic 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 AI-34361 and AI-70337 and a Merit Review from the Veterans Affairs.

² Address correspondence and reprint requests to Dr. George S. Deepe, Jr., University of Cincinnati College of Medicine, 231 Albert Sabin Way, Medical Science Building 7155, Cincinnati, OH 45267-0560. E-mail address: george.deepe{at}uc.edu

³ Abbreviations used in this paper: M, macrophage; Arg-1, arginase 1; DC, dendritic cell; cDC, conventional dendritic cell; MFI, mean fluorescence intensity; iNOS, inducible NO synthase; TipDC, TNF and iNOS-producing DC; i.n., intranasal(ly); WT, wild type; qRT-PCR, quantitative real-time PCR; RQ, relative quantification.