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Migration Dynamics in Leukocyte Transendothelial Endothelial Actin-Binding Proteins and Actin

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Migration Dynamics in Leukocyte Transendothelial Endothelial Actin-Binding Proteins and Actin Th eJournal of Brief Reviews Immunology Endothelial Actin-Binding Proteins and Actin Dynamics in Leukocyte Transendothelial Migration Michael Schnoor The endothelium is the first barrier that leukocytes have Ag-1 and macrophage-1 Ag or the b1-integrin very late Ag-4 to overcome during recruitment to sites of inflamed tis- on leukocytes mediate firm adhesion. Subsequently, leukocytes sues. The leukocyte extravasation cascade is a complex reach the site of transmigration by intraluminal crawling. Leu- multistep process that requires the activation of various kocytes can crawl as much as 60 mm in a macrophage-1 Ag/ adhesion molecules and signaling pathways, as well as ac- ICAM-1–dependent fashion before they transmigrate (2). tin remodeling, in both leukocytes and endothelial cells. Transmigration (also known as diapedesis) occurs either trans- Endothelial adhesion molecules, such as E-selectin or cellularly or paracellularly, with the majority of transmigration ICAM-1, are connected to the actin cytoskeleton via events being across paracellular junctions both in vivo and actin-binding proteins (ABPs). Although the contribu- in vitro (3, 4). Finally, leukocytes have to cross pericytes and tion of receptor–ligand interactions to leukocyte extrav- the basement membrane (BM) to conclude extravasation. This asation has been studied extensively, the contribution of occurs through gaps in the pericyte layer that coincide with endothelial ABPs to the regulation of leukocyte adhe- regions of the BM that contain less extracellular matrix proteins sion and transendothelial migration remains poorly un- and, therefore, pose a thinner barrier for the transmigrating derstood. This review focuses on recently published leukocyte (5, 6). All of these steps require cell movement and evidence that endothelial ABPs, such as cortactin, myo- actin cytoskeletal remodeling in both cell types involved. Thus, sin, or a-actinin, regulate leukocyte extravasation by it seems logical that actin-binding proteins (ABPs) play a central role in the control of the cellular movements involved in controlling actin dynamics, biomechanical properties transmigration. Several ABP-mediated mechanisms in immune of endothelia, and signaling pathways, such as GTPase cells have been described to regulate cellular interactions during activation, during inflammation. Thus, ABPs may serve infection and inflammation (7), but endothelial ABPs have been as targets for novel treatment strategies for disorders largely neglected because the endothelium has long been con- characterized by excessive leukocyte recruitment. The sidered a passive barrier that needs to be breached by leukocytes by guest on October 1, 2021. Copyright 2015 Pageant Media Ltd. Journal of Immunology, 2015, 194: 3535–3541. during extravasation. However, it becomes increasingly clear that the endothelium plays a more active role than previously uring inflammation, the endothelium actively con- anticipated and actively supports immune cells during trans- tributes to leukocyte extravasation by expression of migration. For example, ECs can extend membrane structures D adhesion molecules, release of cytokines, presentation that engulf adhering leukocytes. Several groups identified such of chemokines, and by accommodating leukocyte crawling on its structures that were termed docking structures (8), transmigra- apical surface and transmigration across its cell body or inter- tory cups (9), endothelial apical cups (10), or domes (11). They cellular contacts by “customized” actin dynamics controlling are enriched in clustered ICAM-1 and VCAM-1, actin, and http://classic.jimmunol.org endothelial cell (EC) functionality. ABP (12, 13). Docking structures are believed to strengthen The leukocyte extravasation cascade is a complex multistep leukocyte–endothelial interactions and guide emigrating leuko- process that requires adhesive interactions and dynamic actin cytes, but their exact physiological relevance remains elusive. remodeling in both transmigrating immune cells and ECs The leukocyte extravasation cascade is continuously the topic (Fig. 1). When an inflammatory stimulus arises, proin- of excellent reviews; however, most reviews focused on receptor– flammatory cytokines are produced that induce surface expres- ligand interactions and subsequent signaling mechanisms (3, 6, Downloaded from sion of selectins to mediate leukocyte tethering and rolling (1). 14, 15). Few reviews highlighted the importance of endothelial Expression of ICAM-1 and VCAM-1 on the endothelium and actin remodeling and endothelial ABP for leukocyte transmi- activation of the b2-integrins lymphocyte function-associated gration (16–18). This review provides an update on the Department of Molecular Biomedicine, Center for Research and Advanced Studies of Abbreviations used in this article: ABP, actin-binding protein; AJ, adherens junction; the National Polytechnic Institute, 07360 Mexico City, Mexico BM, basement membrane; EC, endothelial cell; ERM, ezrin/radixin/moesin; LRBC, lateral border recycling compartment; LSP-1, leukocyte-specific protein-1; MLCK, my- Received for publication December 31, 2014. Accepted for publication February 5, osin L chain kinase; TJ, tight junction; VL, ventral lamellipodia. 2015. This work was supported by grants from the Mexican Council for Science and Tech- Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 nology (179895, 207268, and 233395). Address correspondence and reprint requests to Dr. Michael Schnoor, Center for Re- search and Advanced Studies of the National Polytechnic Institute, Department of Molecular Biomedicine, Avenue IPN 2508, San Pedro Zacatenco, Gustavo A. Madero, 07360 Mexico City, Mexico. E-mail address: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.1403250 3536 BRIEF REVIEWS: ACTIN-BINDING PROTEINS REGULATE LEUKOCYTE EXTRAVASATION by guest on October 1, 2021. Copyright 2015 Pageant Media Ltd. FIGURE 1. Endothelial ABPs control leukocyte recruitment at different steps of the leukocyte extravasation cascade. The central panel shows the different steps of http://classic.jimmunol.org the entire leukocyte extravasation cascade. The surrounding panels show, in detail, the receptor–ligand interactions, involved ABPs, and actin-remodeling processes that contribute to each step of the cascade. Numbers in the boxes refer to the respective steps of the cascade as they appear in the central panel. (1–4) Mechanisms by which endothelial ABPs support leukocyte rolling and adhesion. (1) Cortactin binds to E-selectin to support tethering of leukocytes to the endothelial apical surface. (2 and 3) Cortactin, filamin B, a-actinin, and ERM are recruited to ligand-bound ICAM-1 and VCAM-1 to slow down rolling leukocytes and mediate firm adhesion. This may include binding of ERM to contractile actomyosin stress fibers. (4) It has not been studied whether ABPs also support intraluminal crawling. (5) Cortactin, filamin B, a-actinin, and ERM facilitate transmigratory cup formation by supporting ICAM-1/VCAM-1 clustering, RhoG activation [also Rac1 (12), not depicted], and actin remodeling for protrusion formation. VASP and ERM may connect docking structures to actomyosin stress fibers. (6a) Downloaded from Wave-2– and Arp2/3-dependent actin remodeling is required for opening and closure of transmigratory pores to enable transcellular migration. Actin depo- lymerization occurs to create low-resistance regions within the cell. ICAM-1 gets internalized within caveolin-1–enriched caveolae to stabilize the transmigratory pore. ICAM-1 is transcytosed to the basal membrane, where it may serve as receptor for transmigrated leukocytes. (6b) ABPs, such as ZO-1 and a-catenin, which stabilize the endothelial barrier by connecting TJs and AJs to the actin cytoskeleton, need to be disassembled from their adhesion receptors and the cytoskeleton to allow for junction opening. This is accompanied by the formation of contractile actomyosin stress fibers to exert pulling forces on junctions. It is not known whether abluminal crawling (7) and crossing of pericytes and BM (8) require endothelial ABPs. Cav-1, caveolin-1; LER, low expression region. emerging importance of endothelial ABP and actin dynamics rat mesentery are characterized by a circumferential actin rim, for the leukocyte extravasation cascade (Table I). capillaries show diffuse actin staining, and postcapillary ven- ules, a main site of leukocyte extravasation, display a thin Endothelial actin dynamics during leukocyte extravasation peripheral actin ring with few central fibers (19). Under in- The actin cytoskeleton is crucial for endothelial functionality. flammatory conditions, the endothelial actin cytoskeleton Depending on the type of vasculature, ECs contain different needs to be constantly remodeled to accommodate leukocyte forms of F-actin. Under basal conditions, large arterioles of the movement on and across the endothelium. Inflammatory The Journal of Immunology 3537 Table I. Overview of endothelial ABPs that regulate leukocyte extravasation Protein Actin Regulation Effect Mechanisms of Extravasation Regulation Refs. a-Actinins Connect adhesion receptors to actin; actin ↑ a-Actinin-1 and 4 bind directly to ICAM-1 with a-actinin-4 (46) cross-linking supporting transmigration more prominently ↑ a-Actinin-4 regulates EC stiffness, ICAM-1 clustering, and (8, 38) formation of docking structures around adherent leukocytes Arp2/3 Formation of branched actin networks ↑ Arp2/3 inhibition prevents induced occludin endocytosis and (57,
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