Lung resident macrophage subsets in regulating tissue immunity - Resubmission - 1

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Abstract Tissue-resident macrophages are a diverse population of cells that perform specialized functions such as sustaining tissue homeostasis and surveillance. We recently identified a novel subset of pulmonary interstitial macrophages in mice and humans that localize to the lungs and are in close contacts with the innervating nerves. These nerve and airway associated interstitial macrophages (NAMs) are transcriptionally and developmentally distinct from the alveolar macrophages (AMs). In our influenza studies, we found that NAMs proliferate robustly and their absence augmented the inflammatory response following infection. However, we know little to nothing about the functions of NAMs in type 2 immune responses. Our overall goal is to characterize the specific contributions of AMs and NAMs following infection with Nippostrongylus brasiliensis (Nb), an experimental model for type2 immunity against helminths diseases. To this end, we propose to combine multiparametric flow cytometry and imaging with our elegant in vivo models and cutting-edge genomic approaches such as scRNA-seq and ATAC-seq. The first aim of this proposal will characterize specific functions of both AMs and NAMs following an infection with Nb parasites, by using in vivo models with selective depletion of AMs or NAMs or both. In the second aim, we will investigate the mechanisms that underpin specific functions of NAMs in mounting a long-lived anti-parasitic immunity. We will also use genomic approaches to unbiasedly evaluate the chromatin accessibility of AMs and NAMs and correlating transcriptomes that allow for their critical and distinct functions. Our proposed studies will open new avenues of research and can fundamentally change our understanding of the functions and mechanisms related to pulmonary macrophages and can be extended to study other pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD) as well as the current global pandemic COVID19.