Macrophage senescence impairs phagocytosis and phagosome function

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Phagocytosis is an evolutionarily ancient process, which likely originated from the need of single celled organisms to internalize and digest food, and has been preserved as the major mechanism by which macrophages recognize and remove particulates, dying or damaged cells and pathogens. Our lab has recently discovered that non-opsonic phagocytosis (i.e. phagocytosis that does not require the target to be coated by complement, antibodies or other opsonins) by macrophages decreases with age, even though expression of non-opsonic receptors does not change. Furthermore, we have also found age-related changes in the rate of phagolysosomal fusion occur without affecting the pH, proteolytic or oxidative capacity of the phagosome. This delay in phagosome fusion is sufficient to decrease bacterial killing. We have compared the delay of phagolysosomal fusion between macrophages derived from young (20 mo) wildtype (WT) mice and TNF (tumour necrosis factor alpha) knockout mice, and intriguingly, defective macrophage phagocytosis and phagolysosomal maturation does not seem to be due to chronologic age but rather the increase in the inflammatory cytokine TNF. As we age, levels of inflammatory mediators increase in the serum and tissues. Myeloid cells are particularly sensitive to age-associated inflammation. Macrophages derived from old (20+ mo) mice that are deficient in TNF do not lose phagocytic capacity or demonstrate decreased phagolysosomal fusion. By analyzing transcriptional profiles of alveolar macrophages derived from young (3 mo) and old (20+ mo) WT and TNF KO mice, we have found that negative regulators of TNF signalling increase with age in a TNF dependent manner, leading us to hypothesize that this is an adaptation to chronic TNF stimulation that ultimately makes these macrophages less responsive to acute inflammatory events. We have also found that PI3K (phosphoinositide 3-kinase) signalling is compromised in aging macrophages. Although defects in PI3K signalling have been reported in other aging immune cells, the mechanisms by which PI3K signalling is impaired with age in macrophages and the degree to which this impacts phagolysosomal function is not known. Collectively these data support our hypothesis that TNF inhibits phagolysosomal fusion and impairs phagosomal function by increasing expression of negative regulators and altering PI3K signalling pathways. We propose that macrophages do not so much undergo `senescence' (as traditionally described) but rather they adapt to lifelong exposure to the inflammatory microenvironment. This adaptation includes adapting to chronic age-associated inflammation by increasing expression of negative regulators of inflammation. By uncovering specific components of the PI3K and phagolysosomal fusion pathway that are altered by the aging microenvironment, we may uncover whether this unique senescence phenotype is amenable to manipulation.