Phosphoinositide 3-kinase γ mediates microglial phagocytosis via lipid kinase-independent control of cAMP

Schmidt, Caroline; Schneble, Nadine; Müller, Julia; Bauer, Reinhard; Perino, Alessia; Marone, Romina; Rybalkin, Sergei D.; Wymann, Matthias P.; Hirsch, Emilio; Wetzker, Reinhard

doi:10.1016/j.neuroscience.2012.12.036

Cited by 32 publications

(35 citation statements)

References 24 publications

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“…Since p110γ regulates cAMP levels in cardiomyocytes and microglia [32], [33], [34] we tested whether this is the case in macrophages, using ELISA to measure intracellular cAMP levels in LDLR −/− p110γ +/− and LDLR −/− p110γ −/− mouse BMM. Basal cAMP levels were higher in LDLR −/− p110γ −/− compared to LDLR −/− p110γ +/− BMM (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

“…p110γ regulates cyclic adenosine monophosphate (cAMP) levels in cardiomyocytes through a kinase-independent pathway that involves formation of a complex that includes p110γ, its p84/p87 PIKAP regulatory subunit, and the protein phosphodiesterase3B (PDE3B); this complex controls PDE3B-mediated cAMP hydrolysis [32], [33]. A similar p110γ-dependent mechanism was recently shown to mediate microglial phagocytosis via lipid kinase-independent control of cAMP [34]. It is not known whether p110γ regulates cAMP intracellular levels in macrophages.…”

Section: Introductionmentioning

confidence: 99%

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PI3K p110γ Deletion Attenuates Murine Atherosclerosis by Reducing Macrophage Proliferation but Not Polarization or Apoptosis in Lesions

et al. 2013

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PI3K p110γ Deletion Attenuates Murine Atherosclerosis by Reducing Macrophage Proliferation but Not Polarization or Apoptosis in Lesions

et al. 2013

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“…Interestingly, microglia expressing kinase-deficient mutant of PI3Kγ exhibited similar phagocytosis as wild-type cells suggesting a role for kinase-independent function. It is believed that kinase-independent function of PI3Kγ in forming the adaptor AKAP complex with phosphodiesterase would underlie phagocytosis[64]. …”

Section: Pi3kγ As a Scaffold In Other Systemsmentioning

confidence: 99%

Scaffolding Function of PI3Kgamma Emerges from Enzyme's Shadow

Mohan

Prasad

2017

Journal of Molecular Biology

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Traditionally an enzyme is a protein that mediates biochemical action by binding to the substrate and catalyzing the reaction that translates external cues into biological responses. Sequential dissemination of information from one enzyme to another facilitates signal transduction in biological systems providing for feed-forward and feedback mechanisms. Given this view-point, an enzyme without its catalytic activity is generally considered to be an inert organizational protein without catalytic function and has classically been termed as pseudoenzymes. However, pseudoenzymes still have biological function albeit non-enzymatic like serving as a chaperone protein or an interactive platform between proteins. In this regard, majority of the studies have focused solely on the catalytic role of enzymes in biological function overlooking the potentially critical non-enzymatic roles. Increasing evidence from recent studies implicate that scaffolding function of enzymes could be as important in signal transduction as its catalytic activity an antithesis to the definition of enzymes. Recognition of non-enzymatic functions could be critical as these unappreciated roles may hold clues to the ineffectiveness of kinase-inhibitors in pathology, which is characteristically associated with increased enzyme expression. Using an established enzyme phosphoinositide 3-kinase γ (PI3Kγ), we discuss the insights obtained from the scaffolding function and how this non-canonical role could contribute to/alter the outcomes in pathology like cancer and heart failure. Also we hope that with this review, we provide a forum and a starting point to discuss the idea that catalytic function alone may not account for all the actions observed with increased expression of the enzyme.

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“…Given their expression pattern limited to immune cells, p110δ and p110γ have been initially studied preferentially in models of acute and chronic inflammatory diseases, as they have been found M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 7 "partners in crime" in these pathologies (Rommel, Camps, 2007). Nonetheless, recent studies indicate a complex pattern of expression of p110γ, that includes the presence of small amount of the this enzyme in tissues other than immune cells, such as heart, adipose tissue and brain (Becattini et al , 2011, Ghigo et al , 2012, Patrucco et al , 2004, Schmidt et al , 2013.…”

Section: Phosphatidylinositol 3-kinasesmentioning

confidence: 99%