Lung environment in healthy old age shapes the phenotype and CCR2-mediated recruitment of a subset of apoptotic, high-turnover alveolar macrophages

Abstract Immune system changes with healthy aging lead to chronic systemic inflammation termed inflammaging, contributing to age-related pathologies. Alveolar macrophages (AMs) maintain lung homeostasis and health. The impact of inflammaging on AM populations requires further definition. Herein, we examined the effect of healthy old age on the phenotype and ontogeny of AMs from mice, non-human primates and humans. We identify three AM subpopulations in old age, including a CD11c + CD11b + population that increases more than 10-fold across mammalian species, leading to significant changes associated with heightened inflammation and immune dysregulation. RNA-seq analysis identifies distinct transcriptional AM subpopulation profiles. Experiments in mice reveal the importance of the alveolar environment in shaping AM phenotype and recruitment in healthy old age. The old age alveolar environment promotes phenotypic reprogramming of tissue-resident AMs (TRAMs) toward a CD11c + CD11b + state in addition to enhancing CCR2-dependent recruitment of monocyte-derived AMs, which are relatively short-lived and exhibit high turnover due to Fas-mediated apoptosis. These studies provide important insight regarding the impact of the alveolar environment in healthy old age on AM phenotype and function.