title: Phosphoinositide 3-kinase γ affects LPS-induced disturbance of blood-brain barrier via lipid kinase-independent control of cAMP in microglial cells.
abstract: The breakdown of the blood-brain barrier (BBB) is a key event in the development of sepsis-induced brain damage. BBB opening allows blood-born immune cells to enter the CNS to provoke a neuroinflammatory response. Abnormal expression and activation of matrix metalloproteinases (MMP) was shown to contribute to BBB opening. Using different mouse genotypes in a model of LPS-induced systemic inflammation, our present report reveals phosphoinositide 3-kinase γ (PI3Kγ) as a mediator of BBB deterioration and concomitant generation of MMP by microglia. Unexpectedly, microglia expressing lipid kinase-deficient mutant PI3Kγ exhibited similar MMP regulation as wild-type cells. Our data suggest kinase-independent control of cAMP phosphodiesterase activity by PI3Kγ as a crucial mediator of microglial cell activation, MMP expression and subsequent BBB deterioration. The results identify the suppressive effect of PI3Kγ on cAMP as a critical mediator of immune cell functions.
authors.affiliation: Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University, 07745, Jena, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Frister
authors.forename: Caroline
authors.initials: C
authors.lastname: Schmidt
authors.forename: Nadine
authors.initials: N
authors.lastname: Schneble
authors.forename: Michael
authors.initials: M
authors.lastname: Brodhun
authors.forename: Falk A
authors.initials: FA
authors.lastname: Gonnert
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Jörg P
authors.initials: JP
authors.lastname: Müller
authors.forename: Reinhard
authors.initials: R
authors.lastname: Wetzker
authors.forename: Reinhard
authors.initials: R
authors.lastname: Bauer
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002199:Capillary Permeability; D002478:Cells, Cultured; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004396:Coloring Agents / Q000493:pharmacokinetics; D000242:Cyclic AMP / Q000378:metabolism*; D005070:Evans Blue / Q000493:pharmacokinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000201:enzymology / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D015290:Second Messenger Systems; D065166:Sepsis-Associated Encephalopathy / Q000378:metabolism*; D018746:Systemic Inflammatory Response Syndrome / Q000378:metabolism*
chemical_list: D004396:Coloring Agents; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C482199:lipopolysaccharide, E coli O55-B5; D005070:Evans Blue; D000242:Cyclic AMP; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse