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

Abstract

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-1␤, 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. J. Leukoc. Biol. 81: 793-801; 2007.

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

“…Influenza infection of CCR2 Ϫ/Ϫ mice has previously been shown to result in decreased histological indices of pulmonary inflammation and pathology, a decreased number of monocytes/ macrophages in BAL, and a trend toward decreased mortality (19,20). In this study, we find a much greater effect of CCR2 deficiency on inflammation and mortality.…”

“…BAL cells were collected, as described previously (19). Briefly, tracheas of euthanized mice were cannulated with an 18-gauge angiocath connected to a 1-ml syringe and the lungs were flushed with 0.6ϳ0.8 ml of PBS five times.…”

Neonatal Hyperoxia Enhances the Inflammatory Response in Adult Mice Infected with Influenza A Virus

“…MCP-1 expressed by epithelial and endothelial cells, fibroblasts, and macrophages is the major ligand for the C-C chemokine receptor-2 (CCR2) found on leukocytes. As shown by overexpressing MCP-1 in transgenic mice, MCP-1 recruits monocytes and natural killer cells to the lung and protects against bacterial or viral infection (26,(41)(42)(43). Although protective, overexpression of MCP-1 also causes bronchiolitis obliterans on pneumococcal challenge.…”

“…and tumor necrosis factor-a. These cytokines and chemokines were chosen because they stimulate leukocyte recruitment and are known to be induced during influenza A virus infection (22,26,27). In room air-exposed mice, MCP-1 levels increased within 24 hours of infection and became significantly elevated on Day 3 before declining to naive levels by Day 9 ( Figure 6A).…”

“…Although MCP-1 is chemotactic for monocytes and macrophages, studies have led to an appreciation that it also promotes fibrosis in response to bleomycin (28,29) and affects the inflammatory response to influenza A virus infection (26). To determine whether elevated levels of MCP-1 were associated with fibrosis, lung histology was investigated during infection.…”