title: Phosphoinositide 3-kinase γ mediates microglial phagocytosis via lipid kinase-independent control of cAMP.
abstract: Microglial phagocytosis plays a key role in neuroprotective and neurodegenerative responses of the innate immune system in the brain. Here we investigated the regulatory function of phosphoinositide 3-kinase γ (PI3Kγ) in phagocytosis of bacteria and Zymosan particles by mouse brain microglia in vitro and in vivo. Using genetic and pharmacological approaches our data revealed PI3Kγ as an essential mediator of microglial phagocytosis. Unexpectedly, microglia expressing lipid kinase deficient mutant PI3Kγ exhibited similar phagocytosis as wild-type cells. These data suggest kinase-independent stimulation of cAMP phosphodiesterase activity by PI3Kγ as a crucial mediator of phagocytosis. In sum our findings indicate PI3Kγ-dependent suppression of cAMP signaling as a critical regulatory element of microglial phagocytosis.
authors.affiliation: Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07745 Jena, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schmidt
authors.forename: N
authors.initials: N
authors.lastname: Schneble
authors.forename: J P
authors.initials: JP
authors.lastname: Müller
authors.forename: R
authors.initials: R
authors.lastname: Bauer
authors.forename: A
authors.initials: A
authors.lastname: Perino
authors.forename: R
authors.initials: R
authors.lastname: Marone
authors.forename: S D
authors.initials: SD
authors.lastname: Rybalkin
authors.forename: M P
authors.initials: MP
authors.lastname: Wymann
authors.forename: E
authors.initials: E
authors.lastname: Hirsch
authors.forename: R
authors.initials: R
authors.lastname: Wetzker
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism*; D050356:Lipid Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000201:enzymology* / Q000276:immunology; D010587:Phagocytosis / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000242:Cyclic AMP; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517293:Pde3b protein, mouse