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Phosphoinositide 3-Kinase γ Affects LPS-Induced Disturbance of Blood–Brain Barrier Via Lipid Kinase-Independent Control of cAMP in Microglial Cells

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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.

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Acknowledgments

The authors acknowledge Mrs. R.-M., Zimmer for skillful technical assistance, and F. D. Bohmer, for his collegial review of the manuscript. The study was supported by the Deutsche Forschungsgemeinschaft (DFG, Priority Program 1160 and Grant RTG 1715) and by the German Federal Ministry of Education and Research (BMBF; Grant FKZ 01EO1002; Center for Sepsis Control and Care). A.F. is a Ph.D. student of the Jena School for Microbial Communication, Priority Program 1160 of the DFG and supported in part by the Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany. C.S and N.S. are PhD students of the Research Training Group 1715 “Adaptive Stress Responses” Grant RTG 1715 of the DFG.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University, 07745, Jena, Germany

    Adrian Frister, Caroline Schmidt, Nadine Schneble, Jörg P. Müller, Reinhard Wetzker & Reinhard Bauer

  2. Department of Pathology, Helios-Klinikum Erfurt, Erfurt, Germany

    Michael Brodhun

  3. Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany

    Adrian Frister, Falk A. Gonnert, Michael Bauer & Reinhard Bauer

  4. Molecular Biotechnology Center, University of Torino, 10126, Turin, Italy

    Emilio Hirsch

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  1. Adrian Frister
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Correspondence to Reinhard Bauer.

Additional information

Adrian Frister and Caroline Schmidt have contributed equally to this work.

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Frister, A., Schmidt, C., Schneble, N. et al. Phosphoinositide 3-Kinase γ Affects LPS-Induced Disturbance of Blood–Brain Barrier Via Lipid Kinase-Independent Control of cAMP in Microglial Cells. Neuromol Med 16, 704–713 (2014). https://doi.org/10.1007/s12017-014-8320-z

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  • DOI: https://doi.org/10.1007/s12017-014-8320-z

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