title: The role of CD38 in Fcγ receptor (FcγR)-mediated phagocytosis in murine macrophages.
abstract: 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 Ca(2+) through the mobilization of Ca(2+) 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. Ca(2+) data show that pretreatment of J774A.1 macrophages with 8-bromo-cADPR, ryanodine, blebbistatin, and various store-operated Ca(2+) 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 Ca(2+) 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 Ca(2+) and store-operated extracellular Ca(2+) influx.
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, 561-180, Korea.
authors.forename: John
authors.initials: J
authors.lastname: Kang
authors.forename: Kwang-Hyun
authors.initials: KH
authors.lastname: Park
authors.forename: Jwa-Jin
authors.initials: JJ
authors.lastname: Kim
authors.forename: Eun-Kyeong
authors.initials: EK
authors.lastname: Jo
authors.forename: Myung-Kwan
authors.initials: MK
authors.lastname: Han
authors.forename: Uh-Hyun
authors.initials: UH
authors.lastname: Kim
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002460:Cell Line; D036563:Cyclic ADP-Ribose / Q000235:genetics / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000378:metabolism; D010587:Phagocytosis / Q000502:physiology*; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D017452:Receptors, IgG; D036563:Cyclic ADP-Ribose; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium