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Published online before print December 19, 2006

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(Journal of Leukocyte Biology. 2007;81:793-801.)
© 2007 by Society for Leukocyte Biology

Chemokine regulation of the inflammatory response to a low-dose influenza infection in CCR2–/– mice

Torrey Pines Institute for Molecular Studies, San Diego, California, USA

¹ Correspondence at current address: Center for Infectious Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, S-141 86, Stockholm, Sweden. E-mail: mark.wareing{at}ki.se

Influenza virus infections induce chemokines and cytokines, which regulate the immune response. The chemokine receptor CCR2 plays an important role in macrophage recruitment and in the development of T1 immunity. In the present study, we addressed the role of CCR2 in influenza A virus infection. CCR2 knockout (–/–) mice are protected against influenza A virus infection, despite delayed recruitment of macrophages. We show that low-dose influenza infection of CCR2–/– mice leads to increased neutrophilia between Days 5 and 10 after infection and decreased monocyte/macrophage and CD4⁺ T cell recruitment to the lungs between Days 5 and 7 after infection. These changes in leukocyte recruitment did not result from or cause increased viral titers or delayed viral clearance. Neutrophilia in the lungs correlated with increased keratinocyte-derived chemokine (KC) and/or MIP-2 expression in CCR2–/– mice between Days 5 to 10 after infection, although the kinetics of neutrophil recruitment was not altered. MIP-2 mRNA and protein expression was increased three- to fivefold, and KC protein levels were increased two- to threefold in CCR2–/– compared with CCR2 wild-type mice at Day 5 after infection. This preceded the peak neutrophil influx, which occurred 7 days after infection. In vitro studies confirmed that MIP-2 and KC accounted for neutrophil chemotactic activity in the bronchoalveolar lavage. CCR2 deficiency also resulted in increased MIP-1, MIP-1ß, MCP-1, and IFN-inducible protein 10 and decreased RANTES mRNA expression. Furthermore, IL-6 and TNF- cytokine production were elevated after infection. These studies suggest that CCR2 plays a multifactorial role in the development of the immune response to influenza.

Key Words: neutrophils • virus • cell trafficking • lung

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