Macrophage Bcl6 expression promotes viral dissemination and host inflammation during influenza infection

Abstract

Abstract The role of Bcl6 in regulating anti-viral immune responses is relatively unclear currently. Further investigation was hindered by the development of lethal inflammation in global Bcl6 deficient mice. To circumvent this and explore the cell type-specific role of Bcl6 in regulating anti-viral immunity, we have generated myeloid cell-specific Bcl6 deficient mice (Bcl6 cKO) by crossing Bcl6 fl/fl mice to LysMcre mice. In contrast to global Bcl6 deficient mice, Bcl6 cKO mice exhibited no signs of autoimmunity and tissue inflammation under homeostatic conditions. Using a murine influenza A/PR8 (IAV) infection model, we found that Bcl6 cKO mice showed drastically increased host resistance to IAV. We observed that although airway virus titers are comparable between control and Bcl6 cKO mice, Bcl6 cKO mice had greatly diminished IAV spreading in the lungs. Correspondingly, Bcl6 cKO mice developed milder pulmonary inflammation compared to control mice, characterized by the decreased levels of airway cytokines/chemokines and diminished inflammatory cell infiltration into the lungs. Interestingly, alveolar macrophage depletion abrogated the phenotype of decreased host morbidity and mortality to IAV infection in Bcl6 cKO mice, suggesting that Bcl6 deficiency in tissue resident alveolar macrophages mediates the effects of enhanced host resistance to IAV infection. Together, our data suggest that Bcl6 expression in lung resident macrophages dampens the efficient development of pulmonary anti-viral immune responses. Current studies are focused on the cellular and molecular mechanisms by which macrophage Bcl6 expression inhibits host innate and adaptive immunity during IAV infection.