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

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