Abstract
Neutrophils, the most abundant circulating leukocytes in humans have key roles in host defense and in the inflammatory response. Agonist-activated phosphoinositide 3-kinases (PI3Ks) are important regulators of many facets of neutrophil biology. PIP3 is subject to dephosphorylation by several 5’ phosphatases, including SHIP family phosphatases, which convert the PI3K product and lipid second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3) into PI(3,4)P2, a lipid second messenger in its own right. In addition to the leukocyte restricted SHIP1, neutrophils express the ubiquitous SHIP2. This study analyzed mice and isolated neutrophils carrying a catalytically inactive SHIP2, identifying an important regulatory function in neutrophil chemotaxis and directionality in vitro and in neutrophil recruitment to sites of sterile inflammation in vivo, in the absence of major defects of any other neutrophil functions analyzed, including, phagocytosis and the formation of reactive oxygen species. Mechanistically, this is explained by a subtle effect on global 3-phosphorylated phosphoinositide species. This work identifies a non-redundant role for the hitherto overlooked SHIP2 in the regulation of neutrophils, and specifically, neutrophil chemotaxis/trafficking. It completes an emerging wider understanding of the complexity of PI3K signaling in the neutrophil, and the roles played by individual kinases and phosphatases within.
Highlights
Neutrophils are the most abundant circulating leukocytes in humans
This study characterized the function of SHIP2 in the neutrophil, analyzing neutrophils isolated, and bone marrow chimeras generated from a mouse carrying a homozygous Ship2D/D that contained a small deletion in the catalytic domain, which rendered SHIP2 catalytically dead
Unlike with Ship2deficiency, analysis of Ship2D/D neutrophils allowed us to identify neutrophil functions that were dependent on SHIP2 catalytic activity without being confounded by potential scaffold effects, the major phenotypes of Ship2-/- and Ship2D/D mice were very similar [16, 25]
Summary
Neutrophils are the most abundant circulating leukocytes in humans These polymorphonuclear phagocytes provide a first line immune response against infection by invading pathogens and play a key role in the development of the inflammatory response. Neutrophils express a range of G protein coupled chemoattractant/chemokine receptors with the help of which they detect, and quickly react to gradients of chemoattractants, e.g. bacterial peptides. This underpins their ability to leave the blood stream and move directionally (chemotax) towards sources of chemoattractant. PIP3 causes the recruitment to the plasma membrane and activation of PI3K effectors, many of which are expressed in the neutrophil [3]. The localization of PIP3 at the leading edge is one of the earliest molecular events in neutrophil chemotaxis [4, 5], thought to be important for their ability to polarize and subsequently migrate directionally towards a source of chemoattractant
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