Central Role for G Protein-Coupled Phosphoinositide 3-Kinase γ in Inflammation

Abstract

Phosphoinositide 3-kinase (PI3K) activity is crucial for leukocyte function, but the roles of the four receptor-activated isoforms are unclear. Mice lacking heterotrimeric guanine nucleotide-binding protein (G protein)-coupled PI3Kgamma were viable and had fully differentiated neutrophils and macrophages. Chemoattractant-stimulated PI3Kgamma-/- neutrophils did not produce phosphatidylinositol 3,4,5-trisphosphate, did not activate protein kinase B, and displayed impaired respiratory burst and motility. Peritoneal PI3Kgamma-null macrophages showed a reduced migration toward a wide range of chemotactic stimuli and a severely defective accumulation in a septic peritonitis model. These results demonstrate that PI3Kgamma is a crucial signaling molecule required for macrophage accumulation in inflammation.

Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells

“…Even more drastic was the failure of VV-infected DC to mobilize intracellular free calcium after triggering of CCR7. With regard to the interpretation of these results, it has been shown by several groups that the PI3Kc and PKB are essentially required for chemokine-induced migration of mouse leukocytes [35,36,46]. In contrast, the role of the MAPK pathways for chemotaxis is less clear, although its activation via chemokine receptors is well documented [33,[47][48][49].…”

Lipid signalling in disease

“…PI3K , the only class IB PI3K isoform, is activated by subunits of trimeric G proteins that are dissociated by GPCRs to produce transient, but massive, elevations of PtdIns(3,4,5)P 3 . This lipid kinase integrates multiple signals from chemokines, complement fragments, formylated bacterial peptides and other stimuli, and was shown to be essential for chemokine-induced leukocyte migration in vivo [96][97][98] . Therefore, PI3K has become the subject of impressive pharmacological efforts as a target to treat inflammatory disease 5,99 .…”

Signaling mechanisms for regulation of chemotaxis

“…The identification of PI3Kγ, a G protein-regulated PI3K isoform [23,24], led to the hypothesis that chemoattractants may stimulate PIP 3 production via PI3Kγ. To test the hypothesis and determine the significance of PIP 3 in chemoattractant-induced chemotaxis, we and others generated PI3Kγ-null mice [25][26][27]. PI3Kγ-deficiency completely abrogated chemoattractant-induced PIP 3 production in neutrophils, thus demonstrating that PI3Kγ is required for chemoattractant-induced PIP 3 production in mouse neutrophils.…”

“…PI3Kγ-deficiency completely abrogated chemoattractant-induced PIP 3 production in neutrophils, thus demonstrating that PI3Kγ is required for chemoattractant-induced PIP 3 production in mouse neutrophils. In addition, PI3Kγ-deficiency resulted in impaired neutrophil and macrophage chemotaxis in response to a number of chemoattractants [25][26][27]. To better understand the mechanism by which PI3Kγ regulates chemotaxis, we went on examining migratory and polarization characteristics of PI3Kγ-deficient neutrophils in a shallow chemoattractant gradient.…”

“…While PIP 3 and Cdc42 localize F actin formation, they are not required for F actin formation because chemoattractants could still stimulate F actin formation in PI3Kγ-or PIXα-deficient neutrophils [10,26,53]. Thus, the next important question is how the actin polymerization is regulated by chemoattractants.…”