Mechanisms and implications of phosphoinositide 3-kinase δ in promoting neutrophil trafficking into inflamed tissue

Abstract

The phosphoinositide 3-kinase (PI3K) catalytic subunit p110␦ is expressed in neutrophils and is thought to play a role in their accumulation at sites of inflammation by contributing to chemoattractantdirected migration. We report here that p110␦ is present in endothelial cells and participates in neutrophil trafficking by modulating the proadhesive state of these cells in response to tumor necrosis factor ␣ (TNF␣). Specifically, administration of the selective inhibitor of PI3K␦, IC87114, to animals reduced neutrophil tethering to and increased rolling velocities on cytokine-activated microvessels in a manner similar to that observed in mice deficient in p110␦. These results were confirmed in vitro as inhibition of this isoform in endothelium, but not neutrophils, diminished cell attachment in flow. A role for PI3K␦ in TNF␣-induced signaling is demonstrated by a reduction in Aktphosphorylation and phosphatidylinositol-dependent kinase 1 (PDK1) enzyme activity upon treatment of this cell type with IC87114. p110␦ expressed in neutrophils also contributes to trafficking as demonstrated by the impaired movement of these cells across inflamed venules in animals in which this catalytic subunit was blocked or genetically deleted, results corroborated in transwell migration assays. Thus, PI3K␦ may be a reasonable therapeutic target in specific inflammatory conditions as blockade of its activity reduces neutrophil influx into tissues by diminishing their attachment to and migration across vascular endothelium. (Blood.

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

“…Our results reveal a key role of the PI3Kd-TNF axis in mediating leukocyte recruitment into the ischaemic brain post reperfusion. TNF can promote the recruitment and migration of CNS-invading leukocytes across the vascular endothelial barrier 48 . Despite this, the BM chimera experiments carried out in our study reveal that the reduced level of leukocyte infiltration detected in the absence of PI3Kd activity is initiated in the CNS, and does not result from a loss of PI3Kd in circulating leukocytes.…”

ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system

“…Recently, various reports showed that PI3Kβ predominantly contributed to PIP3 production in PTEN (phosphatase and tension homolog deleted on chromosome ten, the catalytic counterpart of PI3K) negative cancers, suggesting the key role of PI3Kβ in the tumorigenesis with PTEN inactivation [37,38] . PI3Kδ and/or γ inactivation leads to a severely impaired immune system [39,40] , and blocks the recruitment of neutrophils to the sites of inflammation [41,42] , suggesting that these two isoforms are involved in the immune system and inflammation. As the counterpart of PI3K, PTEN dephosphorylates PIP3 to produce PIP2.…”

Cytosolic Phospholipase A2-α Is Necessary for Platelet-activating Factor Biosynthesis, Efficient Neutrophil-mediated Bacterial Killing, and the Innate Immune Response to Pulmonary Infection

“…As arachidonate promotes the fusion of complex liposomes with each other as well as with specific granules isolated from human neutrophils (50), it is possible that the defect in bacterial killing induced by the inhibition of cPLA 2 -α activity is due to impaired phagolysosome maturation and failure to deliver antimicrobial factors such as proteolytic enzymes, antimicrobial peptides, and proteins such as defensins and cathelicidins in high concentration to the compartmentalized pathogen. Alternatively, the impaired bacterial killing associated with inhibition or deletion of cPLA 2 -α may be due to defective or suboptimal activation of signaling pathways modulated by arachidonic acid, such as 3-phosphoinositidedependent protein kinase-mediated activation of protein kinase C-ζ (51), whereas protein kinase C-ζ is expressed in neutrophils and has been implicated in phagocytosis (52,53). However, because bacterial phagocytosis was not impaired in neutrophils derived from cPLA 2 -α -deficient mice or in macrophages treated with Pyrrolidine-1 (5), it is possible that cPLA 2 -α participates in the regulation of phagocytosis-independent bacterial killing such as the process mediated by neutrophil extracellular traps (34).…”