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Cell Origin Dictates Programming of Resident Versus Recruited Macrophages During Acute Lung Injury

Mould, KJ;Barthel, L;Mohning, MP;Thomas, SM;McCubbrey, AL;Danhorn, T;Leach, SM;Fingerlin, TE;O'Connor, BP;Reisz, JA;D'Alessandro, A;Bratton, DL;Jakubzick, CV;Janssen, WJ;

Two populations of alveolar macrophages (AMs) co-exist in the inflamed lung: resident AMs that arise during embryogenesis, and recruited AMs that originate postnatally from circulating monocytes. The objective of this study was to determine whether origin or environment dictates the transcriptional, metabolic, and functional programming of these two ontologically distinct populations over the time course of acute inflammation. RNA sequencing demonstrated marked transcriptional differences between resident and recruited AMs affecting three main areas: proliferation, inflammatory signaling, and metabolism. Functional assays and metabolomic studies confirmed these differences and demonstrate that resident AMs proliferate locally and are governed by increased tricarboxylic acid cycle and amino acid metabolism. Conversely, recruited AMs produce inflammatory cytokines in association with increased glycolytic and arginine metabolism. Collectively, the data show that despite co-existing in the same environment, inflammatory macrophage subsets have distinct immunometabolic programs and possess specialized functions during inflammation that associate with cellular origin.