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CCR2⁺ Monocyte-Derived Dendritic Cells and Exudate Macrophages Produce Influenza-Induced Pulmonary Immune Pathology and Mortality¹

Kaifeng Lisa Lin, Yasushi Suzuki^2,*, Hideki Nakano^3,*, Elizabeth Ramsburg and Michael Dee Gunn^4,*,

^* Department of Medicine and Department of Immunology, and Department of Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710

Infection with pathogenic influenza virus induces severe pulmonary immune pathology, but the specific cell types that cause this have not been determined. We characterized inflammatory cell types in mice that overexpress MCP-1 (CCL2) in the lungs, then examined those cells during influenza infection of wild-type (WT) mice. Lungs of both naive surfactant protein C-MCP mice and influenza-infected WT mice contain increased numbers of CCR2⁺ monocytes, monocyte-derived DC (moDC), and exudate macrophages (exMACs). Adoptively transferred Gr-1⁺ monocytes give rise to both moDC and exMACs in influenza-infected lungs. MoDC, the most common inflammatory cell type in infected lungs, induce robust naive T cell proliferation and produce NO synthase 2 (NOS2), whereas exMACs produce high levels of TNF- and NOS2 and stimulate the proliferation of memory T cells. Relative to WT mice, influenza-infected CCR2-deficient mice display marked reductions in the accumulation of monocyte-derived inflammatory cells, cells producing NOS2, the expression of costimulatory molecules, markers of lung injury, weight loss, and mortality. We conclude that CCR2⁺ monocyte-derived cells are the predominant cause of immune pathology during influenza infection and that such pathology is markedly abrogated in the absence of CCR2.

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 P30ES011961, U54AI057157, and U01AI 074529.

² Current address: Chuo-Samaria Hospital, 1-5-4 Tsukishima Chuo-ku, Tokyo 104-0052 Japan.

³ Current address: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.

⁴ Address correspondence and reprint requests to Dr. Michael Dee Gunn, Department of Medicine, Division of Cardiology, Box 3547, Durham, NC 27710. E-mail address: michael.gunn{at}duke.edu

⁵ Abbreviations used in this paper: NOS2, inducible NO synthase; AM, alveolar macrophage; BAL, bronchoalveolar lavage; DC, dendritic cell; DI, double intermediate; exMAC, exudate macrophage; HA, hemagglutinin; IcosL, ICOS ligand; int, intermediate; LDH, lactose dehydrogenase; LN, lymph node; MDCK, Madin-Darby canine kidney; moDC, monocyte-derived DC; SPC, surfactant protein C; TCID, tissue culture infectious dose; WT, wild type.

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