• Neuromolecular medicine · Dec 2014

    Phosphoinositide 3-kinase γ affects LPS-induced disturbance of blood-brain barrier via lipid kinase-independent control of cAMP in microglial cells.

    • Adrian Frister, Caroline Schmidt, Nadine Schneble, Michael Brodhun, Falk A Gonnert, Michael Bauer, Emilio Hirsch, Jörg P Müller, Reinhard Wetzker, and Reinhard Bauer.
    • Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University, 07745, Jena, Germany.
    • Neuromolecular Med. 2014 Dec 1; 16 (4): 704-13.

    AbstractThe 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.

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