The role of CD38 in Fcγ receptor (FcγR)-mediated phagocytosis in murine macrophages

Phagocytosis is a crucial event in the immune system that allows cells to engulf and eliminate pathogens. This is mediated through the action of immunoglobulin (IgG)-opsonized microbes acting on Fcγ receptors (FcγR) on macrophages, which results in sustained levels of intracellular Ca²⁺ through the mobilization of Ca²⁺ second messengers. It is known that the ADP-ribosyl cyclase is responsible for the rise in Ca ²⁺ levels after FcγR activation. However, it is unclear whether and how CD38 is involved in FcγR-mediated phagocytosis. Here we show that CD38 is recruited to the forming phagosomes during phagocytosis of IgG-opsonized particles and produces cyclic-ADP-ribose, which acts on ER Ca ²⁺ stores, thus allowing an increase in FcγR activation-mediated phagocytosis. Ca²⁺ data show that pretreatment of J774A.1 macrophages with 8-bromo-cADPR, ryanodine, blebbistatin, and various store-operated Ca²⁺ inhibitors prevented the long-lasting Ca ²⁺ signal, which significantly reduced the number of ingested opsonized particles. Ex vivo data with macrophages extracted from CD38 ^-/- mice also shows a reduced Ca²⁺ signaling and phagocytic index. Furthermore, a significantly reduced phagocytic index of Mycobacterium bovis BCG was shown in macrophages from CD38^-/- mice in vivo. This study suggests a crucial role of CD38 in FcγR-mediated phagocytosis through its recruitment to the phagosome and mobilization of cADPR-induced intracellular Ca²⁺ and store-operated extracellular Ca²⁺ influx.