Article

Phosphoinositide 3-Kinase γ Mediates Microglial Phagocytosis Via Lipid Kinase Independent Control of cAMP.

Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07745 Jena, Germany.
Neuroscience (Impact Factor: 3.33). 12/2012; DOI: 10.1016/j.neuroscience.2012.12.036
Source: PubMed

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.

0 Bookmarks
 · 
101 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Investigation of signal transduction is of central importance in molecular cell biology. Specific proteins have been identified as predominant mediators of signalling reactions. Part of them exhibits enzymatic activities, which prevalently have been used for their denomination. Recent investigations unveil a plethora of signalling reactions of these signalling enzymes independently on their enzymatic activity. This review argues for reinforced functional analysis of protein interactions of multifunctional signalling enzymes.
    BioSpektrum 06/2013; 19(4).
  • [Show abstract] [Hide abstract]
    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.
    NeuroMolecular Medicine 07/2014; · 3.89 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Atherosclerosis is an inflammatory disease regulated by infiltrating monocytes and T cells, among other cell types. Macrophage recruitment to atherosclerotic lesions is controlled by monocyte infiltration into plaques. Once in the lesion, macrophage proliferation in situ, apoptosis, and differentiation to an inflammatory (M1) or anti-inflammatory phenotype (M2) are involved in progression to advanced atherosclerotic lesions. We studied the role of phosphoinositol-3-kinase (PI3K) p110γ in the regulation of in situ apoptosis, macrophage proliferation and polarization towards M1 or M2 phenotypes in atherosclerotic lesions. We analyzed atherosclerosis development in LDLR(-/-)p110γ(+/-) and LDLR(-/-)p110γ(-/-) mice, and performed expression and functional assays in tissues and primary cells from these and from p110γ(+/-) and p110γ(-/-) mice. Lack of p110γ in LDLR(-/-) mice reduces the atherosclerosis burden. Atherosclerotic lesions in fat-fed LDLR(-/-)p110γ(-/-) mice were smaller than in LDLR(-/-)p110γ(+/-) controls, which coincided with decreased macrophage proliferation in LDLR(-/-)p110γ(-/-) mouse lesions. This proliferation defect was also observed in p110γ(-/-) bone marrow-derived macrophages (BMM) stimulated with macrophage colony-stimulating factor (M-CSF), and was associated with higher intracellular cyclic adenosine monophosphate (cAMP) levels. In contrast, T cell proliferation was unaffected in LDLR(-/-)p110γ(-/-) mice. Moreover, p110γ deficiency did not affect macrophage polarization towards the M1 or M2 phenotypes or apoptosis in atherosclerotic plaques, or polarization in cultured BMM. Our results suggest that higher cAMP levels and the ensuing inhibition of macrophage proliferation contribute to atheroprotection in LDLR(-/-) mice lacking p110γ. Nonetheless, p110γ deletion does not appear to be involved in apoptosis, in macrophage polarization or in T cell proliferation.
    PLoS ONE 08/2013; 8(8):e72674. · 3.53 Impact Factor

Full-text

Download
39 Downloads
Available from
Jun 5, 2014