PMC:3291650 / 25408-28301 JSONTXT

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Alveolar macrophages are also known to phagocytose virus infected apoptotic cells and antibody coated viral particles, further contributing to viral clearance. We could show that BMDM or alveolar macrophages derived from A20myel-KO mice express higher amounts of chemokines, cytokines and type I IFNs compared to wild type mice in response to in vitro infection. Similarly, in vivo infection with IAV resulted in higher levels of primarily neutrophil attracting chemokines such as KC and MIP-2 and several proinflammatory cytokines such as IL-6, TNF and IL-1β in the lungs of A20myel-KO mice compared to wild type mice. This was associated with a selective enhancement of neutrophil recruitment to the bronchoalveolar compartment, and resulted in improved viral clearance later on during infection. Although the role of neutrophils during viral infection is still under debate, recent evidence supports a protective function of these cells during IAV infection [71], [72]. MCP-1 levels were not affected by the absence of A20 in myeloid cells, which is consistent with the notion that airway epithelial cells are the primary source of MCP-1 production during IAV infection [73]. Mice deficient for the MCP-1 receptor CCR2, which is expressed on a subset of circulating monocytes, are protected against IAV infection and display reduced signs of immunopathology [74]–[76]. During IAV infection these monocytes develop into inflammatory dendritic cells or proinflammatory macrophages [77] and are considered major contributors to IAV-induced immunopathology [78]. A20myel-KO mice were protected against a lethal IAV infection, which is rather surprising since an excessive proinflammatory cytokine response and an excessive influx of inflammatory cells is generally believed to be associated with increased lethality [64], [79]. However, the selective effect of A20 deficiency on neutrophil recruitment, without altering inflammatory monocyte (Ly6C+ CD11b+) recruitment, further support the idea that monocytes and not neutrophils are major contributors to IAV-associated immunopathology and lethality 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