The role of brain endothelial MAP kinases in ICAM-1-mediated lymphocyte transmigration

Doctoral thesis English OPEN
Hudson, N. (2012)
  • Publisher: UCL (University College London)

Leukocyte migration from the blood vessel, across the vascular wall and into the tissue underneath occurs in both an inflammatory response as well as immunosurveillance. During this process multiple adhesive interactions occur between leukocytes and vascular endothelial cells (ECs). The EC itself is rendered compliant to transmigration following inside-out signalling in response to leukocyte adhesion altering the activity of a number of different cellular components including the actin cytoskeleton, Rho GTPases and various protein kinases. For this, adhesion to endothelial intercellular adhesion molecule-1 (ICAM-1/CD54) is particularly important and the focus of this study. Indeed, previous work in our lab has shown that endothelial ICAM-1 signalling controls lymphocyte diapedesis by modulating interendothelial VE-cadherin (VEC) junction phosphorylation via a pathway involving calcium, AMP kinase and nitric oxide synthase (eNOS). In this study, I have investigated if ICAM-1-mediated endothelial mitogen-activated protein (MAP) kinases activation played a role during lymphocyte transmigration across brain microvascular ECs. All three MAP kinases, namely ERK, JNK and p38, were found to be activated in response to ICAM-1 engagement, however only JNK was important for lymphocyte transmigration. Significantly, specific neutralisation experiments using small-molecule inhibitors or dominant-negative plasmids inhibiting JNK resulted in inhibition of transmigration. Activation of JNK required Src, Rho GTPase, MKK7 and protein kinase C (PKC), with all these components also found to be important for lymphocyte transmigration. I further demonstrate that this novel pathway led to the phosphorylation of the actin-associated protein paxillin and its association with VEC. Ultimately this triggered VEC internalisation, suggesting that adherens junction modulation is an important element during transendothelial leukocyte migration. Furthermore, this also suggests that at least two endothelial signalling pathways (JNK-paxillin and eNOS-VEC) converge and cooperate to regulate ICAM-1-mediated lymphocyte transmigration.
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