Discovery of a novel subset of lung resident macrophages that regulate pathogen clearance and immune homeostasis after respiratory infection

Abstract The importance of tissue resident macrophages (TRMϕ) for pathogen clearance and homeostasis is beginning to emerge. However, our understanding of the multifaceted roles these macrophages play in mucosal tissues such as the lung remains incomplete. Currently the major population of TRMϕs in the lung is known to be alveolar macrophages (AMϕ) that express CD11c and CD169. Here we report a novel subset of CD169+ lung resident macrophages that are phenotypically and developmentally distinct from the alveolar or interstitial macrophages. These novel TRMϕ were CD169+CD11C−CX3CR1+Ly6C−CSF−1R+. A remarkable quality of these TRMϕs was their geographical location, which was important for their function. They were exclusively localized around the airways of the lung close to the airway epithelial cells. These airway-associated macrophages (AAMϕ) were radio-resistant, self-renewing and failed to recirculate. To determine the function of lung TRMϕs, we used genetic mouse models and bone marrow chimeric mice to exclusively deplete AMϕ or AAMϕ following influenza infection. We show that AAMϕ cell numbers dramatically increased during infection due to local proliferation and differentiation of infiltrating monocytes. Depletion of CD169+ Mϕ in mice during influenza infection resulted in elevated morbidity. In the absence of CD169+ Mϕ, we observed dramatic changes in the recruitment of innate immune cells such as neutrophils and monocytes in the lungs following infection. Overall, our study relates structure to function at a fundamental level and provides essential insights into a novel subset of AAMϕ in the lung that along with alveolar Mϕ are crucial in mediating protection and maintaining immune homeostasis during influenza infection.