Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils

Wang, Shijun; Voisin, Mathieu-Benoı̂t; Larbi, Karen Y.; Dangerfield, John A.; Scheiermann, Christoph; Tran, Maxine; Maxwell, Patrick H.; Sorokin, Lydia; Nourshargh, Sussan

doi:10.1083/jcb1736oia11

Cited by 37 publications

(51 citation statements)

References 34 publications

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“…The latter is associated with structural changes in the interendothelial adhesion structures and EC cytoskeleton [5,7,8]. Cross-linking of adhesion molecules such as CD54 or CD106 is shown to mediate signals that lead to EC actin cytoskeleton remodeling [9][10][11][12].…”

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confidence: 99%

Endothelial IQGAP1 regulates efficient lymphocyte transendothelial migration

2009

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Leukocyte movement from the blood to the tissues is a fundamental process in acute and chronic inflammatory diseases. While the role of endothelial cells (EC) to recruit leukocytes to sites of inflammation is well known, the mechanisms that control remodeling of EC shape and adhesive contacts during leukocyte transendothelial migration (TEM) are not completely understood. We studied the role of IQGAP1, an adaptor protein that binds to filamentous-actin and microtubules (MT) at interendothelial junctions, during lymphocyte TEM. EC IQGAP1 knockdown decreases MT tethered to the adherens junction, and decreases lymphocyte TEM to $70% (po0.05) versus control. Similarly, loss of adherens junction-associated MT induced by brief nocodazole (ND) treatment decreases lymphocyte TEM to $65% of control (po0.01). Confocal microscopy imaging indicates that EC IQGAP1 knockdown and MT depolymerization both result in lymphocyte accumulation above the vascular endothelial cadherin (VE-cadherin) junctions and reduces the fraction of adherent lymphocytes that complete diapedesis across interendothelial cell junctions. However, we observe no change in VE-cadherin gap formation underlying adherent lymphocytes among control, IQGAP1 knockdown, or MT depolymerised EC monolayers. These data indicate that IQGAP1 contributes to MT stability at endothelial junctions. Further, IQGAP1 is involved in junction remodeling required for efficient lymphocyte diapedesis, independent of VE-cadherin gap formation.Key words: Adherens junctions . Cytoskeleton . IQGAP1 Supporting Information available online IntroductionLeukocyte extravasation is fundamental to the development of many immune responses including solid-organ allograft rejection. In this process, leukocytes leave the bloodstream and migrate into tissues through the endothelial cells (EC) that line the walls of vessels, i.e. leukocytes undergo transendothelial migration (TEM). Whereas the specific adhesion molecules, chemoattractants, and possibly signaling pathways involved in TEM are unique among different subgroups of leukocytes and vascular beds, the interaction between leukocytes and EC during TEM can be generalized into a multicascade event, described in recent reviews [1][2][3]. EC and leukocyte adhesion molecules mediate tethering and rolling of leukocytes on EC followed by chemokinemediated leukocyte activation, then firm adhesion to the EC. Finally, adherent leukocytes crawl on the surface of endothelium, undergo diapedesis, and enter tissues by mechanisms that are not fully understood.Leukocyte transmigration may occur by either a transcellular, through EC, or paracellular route, between adjacent EC [4][5][6]. 204The latter is associated with structural changes in the interendothelial adhesion structures and EC cytoskeleton [5,7,8]. Cross-linking of adhesion molecules such as CD54 or CD106 is shown to mediate signals that lead to EC actin cytoskeleton remodeling [9][10][11][12]. These signaling cascades promote structural changes in interendothlelial junctions, which might be requ...

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confidence: 99%

Endothelial IQGAP1 regulates efficient lymphocyte transendothelial migration

2009

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“…For example, they have a pathfinding role in nerve growth cones and endothelial tip cells during angiogenesis. 45 Leukocytes have been observed to cross the basement membrane at regions where there are lower levels of some matrix proteins 46 and it is tempting to speculate that the filopodia extended by T cells are probing the basement membrane for these regions.…”

Section: A Possible Role Of Rhoa In Filopodia During T Cell Temmentioning

confidence: 99%

Multiple roles for RhoA during T cell transendothelial migration

Heasman

Ridley

2010

Small GTPases

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t cells need to cross endothelial barriers during immune surveillance and inflammation. this involves t-cell adhesion to the endothelium followed by polarization and crawling with a lamellipodium at the front and contractile uropod at the back. t cells subsequently extend lamellipodia and filopodia under the endothelium in order to transmigrate. rho Gtpases play key roles in cell migration by regulating cytoskeletal dynamics and cell adhesion. we have found that the rho Gtpase rhoa is required for efficient t-cell polarization and migration on endothelial cells as well as transendothelial migration. rhoa-depleted cells lack both lamellipodia and uropods, and instead have narrow protrusions extending from a rounded cell body. using a rhoa activity biosensor, we have shown that rhoa is active at the leading edge in lamellipodia and filopodia of crawling and transmigrating t cells, as well as in the uropod. in lamellipodia, its activity correlates with both protrusion and retraction. we predict that rhoa signals via the formin mdia1 during lamellipodial protrusion whereas it induces lamellipodial retraction via the kinase rocK and actomyosin contractility. we propose that different guanine-nucleotide exchange factors (GEfs) are responsible for coordinating rhoa activation and signaling in different regions of transmigrating t cells. IntroductionDuring inflammation leukocytes are recruited from the vasculature into tissues using a specialized migratory pathway. Rho GTPase family proteins are key regulators of cytoskeletal dynamics and cell migration, 3 and thus would be expected to contribute to the process of TEM. Most Rho GTPases cycle between an inactive, GDP-bound form and an active, GTP-bound form, which interacts with and activates downstream targets. Rho GTPases are stimulated by guanine nucleotide exchange factors (GEFs), which stimulate exchange of GDP for GTP and inactivated by GTPaseactivating proteins (GAPs), which stimulate GTP hydrolysis.In our recent paper we used an RNAi screen to identify which Rho GTPases are important for T cell TEM. 4 We found that knockdown of RhoA induced the strongest inhibition of this process and so subsequently examined the role of RhoA in detail during both T cell crawling on EC and subsequent TEM. Significantly, active RhoA was observed at both the front and back of polarized T cells as they crawled on EC and transmigrated, as well as in dynamic puncta in the basal membrane and filopodia extending beneath the endothelium of transmigrating cells ( fig. 1). Here we discuss the implications of these findings in the context of current understanding of RhoA signaling and the potential function of these cellular processes in T-cell migration. Extra View to: Heasman SJ, Carlin LM, Cox S, Ng T, Ridley AJ. Coordinated RhoA signaling at the leading edge and uropod is required for T cell transendothelial migration.

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“…Interestingly, a similar inflammation-induced thinning of the BM was already reported for BVs. 41 It was recently shown that under steady-state conditions, integrin-deficient DCs homed as efficiently to dLNs as WT DCs, suggesting that interactions between DC-expressed integrins and LEC-expressed integrin ligands were not important in the process of DC migration in the interstitium and into or within LVs. 2 By contrast, an earlier study identified a role for inflammation-induced ICAM-1 or VCAM-1 in mediating DC migration from inflamed skin to dLNs.…”

Section: Rock In DC Migration and Intralymphaticmentioning

confidence: 99%

Differential requirement for ROCK in dendritic cell migration within lymphatic capillaries in steady-state and inflammation

Nitschké

Aebischer

Abadier

et al. 2012

Blood

135

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Dendritic cell (DC) migration via lymphatic vessels to draining lymph nodes (dLNs) is crucial for the initiation of adaptive immunity. We imaged this process by intravital microscopy (IVM) in the ear skin of transgenic mice bearing redfluorescent vasculature and yellowfluorescent DCs. DCs within lymphatic capillaries were rarely transported by flow, but actively migrated within lymphatics and were significantly faster than in the interstitium. Pharmacologic blockade of the Rho-associated protein kinase (ROCK), which mediates nuclear contraction and de-adhesion from integrin ligands, significantly reduced DC migration from skin to dLNs in steady-state. IVM revealed that ROCK blockade strongly reduced the velocity of interstitial DC migration, but only marginally affected intralymphatic DC migration. By contrast, during tissue inflammation, ROCK blockade profoundly decreased both interstitial and intralymphatic DC migration. Inhibition of intralymphatic migration was paralleled by a strong up-regulation of ICAM-1 in lymphatic endothelium, suggesting that during inflammation ROCK mediates de-adhesion of DC-expressed integrins from lymphatic-expressed ICAM-1. Flow chamber assays confirmed an involvement of lymphatic-expressed ICAM-1 and DC-expressed ROCK in DC crawling on lymphatic endothelium. Overall, our findings further define the role of ROCK in DC migration to dLNs and reveal a differential requirement for ROCK in intralymphatic DC crawling during steadystate and inflammation. (Blood. 2012; 120(11):2249-2258) IntroductionDendritic cells (DCs) are important in the initiation of adaptive immune responses. In peripheral tissues, such as the skin, DCs take up antigen, mature, and migrate via lymphatic vessels (LVs) to draining lymph nodes (dLNs), where they present antigen to resting T cells. Although this migration pattern has been known for more than 20 years, 1 DC migration into LVs is only now starting to be unraveled at the cellular level using live imaging technologies. [2][3][4] Before transmigrating across the lymphatic endothelium, DCs first need to squeeze through preformed, narrow pores present in the lymphatic basement membrane (BM). 3 DC entry into LVs is thought to occur at the level of primary lymphatic capillaries, which feature discontinuous cell junctions with "button"-like accumulations of cell adhesion molecules. 5 At the sites of such buttons, lymphatic endothelial cells (LECs) partially overlap and generate open flaps, through which leukocytes enter into lymphatics. 3,5 The most prominent mediator of DC migration into afferent lymphatics is CCL21, a chemokine constitutively expressed in LVs. 6,7 More recently, also other LEC-expressed molecules that mediate DC migration via LVs to dLNs have been identified. [8][9][10][11] Notably, ICAM-1 and VCAM-1, which are up-regulated in LVs during inflammation, 8,12 have been implicated in this process. 8 Intriguingly, experiments performed with pan-integrin knockout DCs revealed that DC migration to dLNs in steady-state was integrin-independent. 2 This ...

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Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils

Cited by 37 publications

References 34 publications

Endothelial IQGAP1 regulates efficient lymphocyte transendothelial migration

Endothelial IQGAP1 regulates efficient lymphocyte transendothelial migration

Multiple roles for RhoA during T cell transendothelial migration

Differential requirement for ROCK in dendritic cell migration within lymphatic capillaries in steady-state and inflammation

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