Metabolism and ontogeny of alveolar macrophages contribute to peripheral trained immunity and confer protection against <i>Mycobacterium tuberculosis</i>

Abstract Lung alveolar macrophages (AMs) reside in the space and function as key sentinels to promote lung immune resilience. Notably, major cell target of early Mycobacterium tuberculosis (Mtb) infection, AMs provide a permissive cellular niche for rapid Mtb growth. However, mechanisms which regulate permissiveness during infection remain elusive. Here, we aimed identify intrinsic features that could be exploited protective trained immunity against Mtb. Employing an intranasal β-glucan exposure model, observed mice treated with acquire sustained enhanced activation well metabolic reprogramming. These phenotypes are attributed development monocyte-derived (MoAMs) CCR2- innate-derived IFN-γ dependent manners. Intriguingly, MoAMs rather than pre-existing exhibit canonical immunity, including shift towards glycolysis, cytokine production phagocytic activity. Chromatin accessibility analysis further revealed ontogeny dictates their epigenetic landscape. Lastly, treatment significantly reduces burden lung, associated AM functions increased productions proinflammatory cytokines from MoAMs. results suggest while tissue signals restrict plasticity limit capability being reprogrammed vaccination therapeutic purposes, metabolism two essential regulating infection. Furthermore, our study also highlights importance macrophage novel determining factor peripheral immunity. Supported by grants American Association (CA-828143) NIH (P20GM103625)