Journal
IMMUNOLOGY AND CELL BIOLOGY
Volume 99, Issue 6, Pages 622-639Publisher
WILEY
DOI: 10.1111/imcb.12447
Keywords
adhesion molecules; AKT; CCL2; E‐ selectin; macrophage activation; mTOR
Categories
Funding
- Cancer Council Queensland [1052400, 1147317]
- National Health and Medical Research Council of Australia (NHMRC) [1083198, 543706, 1130273]
- Career Development Fellowship [1033736]
- Queensland Smart State Fellowship [MN127938]
- Equity Trustees
- NHMRC [1108352, 1136130]
- Australian government
- Mater Foundation
- National Health and Medical Research Council of Australia [1130273, 1136130, 1108352, 1083198] Funding Source: NHMRC
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The study revealed that E-selectin plays a role in the early stages of immune activation by inducing phosphorylation of AKT and nuclear factor-kappa B in mouse macrophages, leading to enhanced activation and modulation of immune responses.
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-kappa B 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.
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