Adhesion to E‐selectin primes macrophages for activation through AKT and mTOR

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Abstract
The endothelial adhesion protein E‐selectin/CD62E is not required for leukocyte homing, unlike closely related family member P‐selectin/CD62P. As transmigration through the endothelium is one of the first steps in generating a local immune response, we hypothesized that E‐selectin may play additional roles in the early stages of immune activation. We found contact with E‐selectin, but not P‐selectin or vascular cell adhesion molecule 1 (CD106), induced phosphorylation of protein kinase B (AKT) and nuclear factor‐κB in mouse bone marrow‐derived macrophages (BMDMs) in vitro. This occurred within 15 min of E‐selectin contact and was dependent on phosphatidylinositol‐3 kinase activity. Binding to E‐selectin activated downstream proteins including mammalian target of rapamycin, p70 ribosomal protein S6 kinase and eukaryotic translation initiation factor 4E‐binding protein 1. Functionally, adhesion to E‐selectin induced upregulation of CD86 expression and CCL2 secretion. We next asked whether contact with E‐selectin impacts further BMDM stimulation. We found enhanced secretion of both interleukin (IL)‐10 and CCL2, but not tumor necrosis factor or IL‐6 in response to lipopolysaccharide (LPS) stimulation after adhesion to E‐selectin. Importantly, adhesion to E‐selectin did not polarize BMDMs to one type of response but enhanced both arginase activity and nitric oxide production following IL‐4 or LPS stimulation, respectively. In cultured human monocytes, adhesion to E‐selectin similarly induced phosphorylation of AKT. Finally, when E‐selectin was blocked in vivo in mice, thioglycollate‐elicited macrophages showed reduced CD86 expression, validating our in vitro studies. Our results imply functions for E‐selectin beyond homing and suggest that E‐selectin plays an early role in priming and amplifying innate immune responses.
Funding Information
  • Cancer Council Queensland (1052400, 1147317)
  • National Health and Medical Research Council (1033736, 1083198, 1130273, 543706)

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