Figure 8.

Roles of CCR2+ inflammatory monocytes in highly pathogenic IAV infection. We achieved varying degrees of weight loss with mildly, moderately or severely inflamed lungs in mice inoculated with the 141, SOIV or PR8 strains. These H1N1 infection models with variable efficiencies of viral clearance result in the accumulation of varying numbers of CCR2+ inflammatrory monocytes, which are highly associated with the generation of a cytokine storm and expression of iNOS. In the early phase of infection, we propose that a small number of infiltratng CCR2+ inflammatory monocytes are infected with IAV and respond to autocrine and/or paracrine IFNβ, which induces the expression of the CCR2 ligands, CCL2, CCL7 and CCL12. Recruited CCR2+ inflammatory monocytes drive further recruitment of CCR2+ inflammatory monocytes from the BM to the lung through CCR2-dependent chemotaxis. In the late phase of infection, impaired clearance of PR8 virus leads to spread of infection to recently arrived CCR2+ inflammatory monocytes and to sustained production of the IFNAR1-IFNβ signaling axis-induced CCR2 ligands, which cause infiltrating CCR2+ inflammatrory monocytes to amplify their own recruitment continuously through the IFNAR1-dependent chemokine feedback loop.