**6.4 Age-associated change in alveolar macrophage subpopulation**

Lung macrophages (a crude fraction containing both alveolar and interstitial macrophages) from aged mice has a high baseline level of dysfunctional expression of IFN-γ target genes, and IFN-γ fails to boost ex vivo *M. tuberculosis* infectioninduced phagosome-lysosome fusion and IL-12 production in aged mouse cells [105]. The so-called inflammaging phenotype in alveolar macrophages and lining fluid extends further to a wide variety of pro-inflammatory cytokine and chemokine levels, which was caused by an increased subpopulation of CD11b-positive alveolar macrophages originating from peripheral monocytes [106]. Such inflammaging systemically occurs in humans as well [107]. Although inflammaging of alveolar macrophages has been suggested to increase susceptibility to *M. tuberculosis* in the elderly [105, 106, 108, 109], the relationship between inflammaging and vulnerability to acute LRTIs remains to be elucidated [110]. Further, recruitment of circulating monocytes to the alveoli has been demonstrated in several longitudinal studies using mice in which bone marrow-derived monocytes were labeled with specific reporters [111, 112] and was systematically discussed in a review article [113]. In contrast, another recent genetic lineage-tracing analysis using CD45.1/CD45.2 chimeric mice yielded contradictory observations that the proportion of CD45.1-positive monocytederived macrophages and CD45.2-positive tissue-resident macrophages in the alveoli were preserved throughout life [114]. However, when infected with a sublethal dose of the influenza A virus, monocyte-derived macrophages were recruited into the alveoli, and the macrophages persisted for at least 60 days. These results underpin previous findings that alveolar macrophages are not replenished by bone marrow-derived monocytes [35]. Further experimental results and an integrated understanding are required to clarify the age-associated changes in alveolar macrophage subpopulations and their role in susceptibility to acute LRTIs.
