Friday, March 24, 2023
Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™
ABIM Diplomates - maximum of 1.00 ABIM MOC points
This activity is intended for hematologists and other specialists in pathophysiologic mechanisms underlying inflammatory and infectious disease.
The goal of this activity is for learners to be better able to describe how molecular mechanisms underlying the initial interactions between leukocytes and endothelial cells are linked to opening of the endothelial barrier, based on a mouse model.
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Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.
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CME / ABIM MOC Released: 7/21/2022
Valid for credit through: 7/21/2023
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The extravasation of leukocytes is a critical step during inflammation that requires the localized opening of the endothelial barrier. This process is initiated by the close interaction of leukocytes with various adhesion molecules such as ICAM-1 on the surface of endothelial cells. Here we reveal that mechanical forces generated by leukocyte-induced clustering of ICAM-1 synergize with fluid shear stress exerted by the flowing blood to increase endothelial plasma membrane tension and to activate the mechanosensitive cation channel PIEZO1. This leads to increases in [Ca2+]i and activation of downstream signaling events including phosphorylation of tyrosine kinases sarcoma (SRC) and protein tyrosine kinase 2 (PYK2), as well as of myosin light chain, resulting in opening of the endothelial barrier. Mice with endothelium-specific Piezo1 deficiency show decreased leukocyte extravasation in different inflammation models. Thus, leukocytes and the hemodynamic microenvironment synergize to mechanically activate endothelial PIEZO1 and subsequent downstream signaling to initiate leukocyte diapedesis.
The endothelial cell layer is a tight barrier for cells in the circulation. However, during inflammation, leukocytes can transmigrate the endothelium and extravasate in the perivascular space, a process that involves a well-coordinated cascade of events. This includes initial leukocyte capture and rolling, firm adhesion, and crawling, which are then followed by breaching of the endothelial barrier and the extravasation.[1–3] The molecular mechanisms that control and mediate the initial interactions between leukocytes and endothelial cells are well characterized and involve interactions between endothelial selectins and glycoproteins of leukocytes during capture and rolling steps, whereas arrest, firm adhesion, and crawling are mediated mainly by integrins on leukocytes that bind to endothelial ICAM-1 and VCAM-1 and induce their clustering.[2,4–6] How these initial processes are linked to the opening of the endothelial barrier, which requires the remodeling of endothelial adherens junctions and endothelial cell contraction,[7–12] is, however, poorly understood.
Opening of endothelial junctions and endothelial cell contraction during leukocyte transmigration require activation of endothelial signaling pathways, and several studies have shown that leukocytes induce an increase in the cytosolic Ca2+ concentration in endothelial cells.[13–18] This calcium signal is not necessary for leukocyte adhesion but is required to induce transendothelial migration.[13–15] ICAM-1 has been shown to be involved in lymphocyte-induced Ca2+ transients in endothelial cells,[15] and, more recently, the transient receptor potential channel C6 (TRPC6) has been shown to be required for endothelial calcium transients induced by neutrophils and for transendothelial migration,[19] but how leukocytes induce endothelial Ca2+ transients is still unclear.
The Piezo proteins PIEZO1 and PIEZO2 are mechanically activated cation channels that form homotrimeric complexes,[20–22] which are sufficient to mediate mechanically induced currents.[20] PIEZO1 has been shown to be gated directly by changes in membrane tension[23–25] and to mediate multiple cellular processes including endothelial flow sensing.[26–28] In this study, we found that PIEZO1 is required for leukocyte extravasation by coincidentally sensing increased membrane tension induced by flow and ICAM-1 clustering. The subsequent activation of signaling pathways then results in the localized opening of the endothelial barrier.
