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

Immune system changes with age 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 age on the phenotype and ontogeny of AMs from mice, non-human primates and humans. We identify three AM subpopulations in old age, two of which increase more than 10-fold, leading to significant functional consequences associated with heightened inflammation and immune dysregulation. RNA-seq analysis identifies unique transcriptional AM subpopulation profiles. Adoptive transfer experiments reveal the importance of the alveolar environment in AM recruitment and phenotypic change in old age. Monocyte-derived AM recruitment in old age requires CCR2 and leads to relatively short-lived AMs with high turnover due to Fas-mediated apoptosis. These studies provide new insight on the impact of the alveolar environment in healthy old age on AM phenotype and function.