Shah, M.; Kirthivasan, N.; Chakraborty, S.; Krishnan, Y.; Jhunjhunwala, S.

In macrophages, it is generally assumed that without active escape mechanisms, all phagocytosed cargo eventually reaches lysosomes. Yet, the influence of specific ligands, like lipopolysaccharide (LPS), on phagosome maturation is unclear. Here, using sterile, non-immunogenic particles as model cargo phagocytosed by macrophages, we show that in the absence of an external signal, less than half the phagosomes fuse with lysosomes. By quantifying phagosome maturation in terms of lysosomal localization and mapping lumenal pH dynamics, we find that early events triggered by LPS-induced signaling enhance both cargo delivery to lysosomes and phagosome acidification rates. We demonstrate that stress-activated p38 alpha mitogen-activated protein kinase (p38 MAPK) is important for this signaling event. Other signals known to activate p38 MAPK such as flagellin, IgG and albumin also enhance lysosomal delivery of phagocytosed cargo. Our work indicates that the maturation of phagosomes in macrophages is enhanced by the presence of specific ligands on the cargo, which activate cell surface receptors that signal via p38 MAPK.