Influence of aging on the phenotype and function of alveolar macrophages

Abstract

Abstract Aging is associated with a decline in immune function (immunosenescence), resulting in increased susceptibility to infectious diseases, malignancies, and autoimmunity. However, the immunosenescence paradigm does not explain increased circulating pro-inflammatory cytokines and increased tissue expression of pro-inflammatory genes with aging. These observations have led to a second paradigm, termed inflammaging, in which chronic, low grade inflammation develops with increasing age. Published studies have shown that inflammaging also occurs in the lung. However, the influence of inflammaging on alveolar macrophage (AM) phenotype and function is largely unexplored. In this study, we examined the phenotype and function of AMs isolated from young (3 months) and old (18 months) C57BL/6 mice. Phenotypic analysis of AMs by flow cytometry showed that in young mice there is a major AM population that is CD11c+CD11b− and a minor population that is CD11c+CD11b+. In young mice, this minor population represents 1.3% of AMs. However, in old mice the percentage of this minor population is significantly higher (4.9%, p <0.0001). The CD11c+CD11b+ AMs have higher expression of several cell surface markers, e.g. MHC II and CD64, indicating that these AMs are in a more prime or activated state. Functional studies of these AMs stimulated with LPS, PamCSK4, or infected with Mycobacterium tuberculosis show significant spontaneous production of IFN-β, CCL2, and IL-10 that is prolonged in old mice and increased further by stimulation with ligands or infection. Our studies indicate that inflammaging in the lung primes AMs, resulting in robust production of key cytokines upon stimulation that potentially alter host susceptibility.