Alveolar macrophage subpopulations display unique inflammatory signatures in old age

Identification: Pahari-Susanta


Alveolar macrophage subpopulations display unique inflammatory signatures in old age
Alveolar macrophage subpopulations display unique inflammatory signatures in old age

Susanta Pahari1, Miranda Lumbreras1, Eusondia Arnett1, Hao Zhang2, Hong Cai2, Yufeng Wang2, Diego Jose Maselli-Caceres3, Jay Peters3, William P. Lafuse4, Jordi B. Torrelles1, Joanne Turner1, and Larry S. Schlesinger1

 1Texas Biomedical Research Institute, San Antonio, TX 78227
 2Department of Biology, South Texas Center for Emerging Infectious diseases, University of Texas at San Antonio, TX 78249
 3Division of Pulmonary and Critical Care Medicine, UT Health Science Center, San Antonio, TX 78207
 4Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210

Aging is associated with low-grade chronic inflammation. Mouse/human alveolar macrophages (mAMs/hAMs) maintain lung homeostasis and are often the first cell type exposed to invading pathogens reaching the alveolar space. We have previously identified an increased CD11c+ CD11b+ mAM subpopulation in old mice expressing monocytic markers, a unique inflammatory signature and enhanced M. tuberculosis growth, suggesting a potential sentinel population for tuberculosis susceptibility in old age (J Immunol 203:2252, 2019). Herein, we examined the effect of aging on the phenotype of isolated mAMs/hAMs from young (3 month)/old (18 month) mice and healthy adult (20-50 y)/ elderly (≥65 y) humans. We identified three hAM subpopulations in the elderly: a major resident CD11c+ CD11b- population and two minor CD11c+ CD11b+, CD11c- CD11b+ populations that are increased more than 10-fold (n=19) in elderly humans. CD11c+ CD11b+ hAMs have higher expression of both immunoregulatory and inflammatory markers than CD11c+ CD11b- hAMs. Flow cytometry revealed elevated CD206, CD64, HLA-DR, Fas, and CX3CR1; and qRT-PCR revealed higher expression of TNF, CD206, FAS, CX3CR1, CCL2, NOS2, TLR2, TLR9, IFN-β, HIF-1α, IDO1, and IL-10 on CD11c+ CD11b+ elderly AMs. CD11c+ CD11b+ hAMs also expressed CD14, CD16, and CD115, suggesting monocytic origin; these were absent in CD11c+ CD11b- resident hAMs. Adoptive transfer experiments in mice reveal the importance of the alveolar environment in AM recruitment and differentiation in old age. RNA-seq analysis demonstrates unique transcriptional signatures of 3 subpopulations of mAMs in old mice. RNA-seq of hAMs is ongoing. These studies are defining the impact of the alveolar environment in old age on AM phenotype and function. P01AG051428


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