The adhesion molecule L1 regulates transendothelial migration and trafficking of dendritic cells

Maddaluno, Luigi; Verbrugge, Sue Ellen; Martinoli, Chiara; Matteoli, Gianluca; Chiavelli, Andrea; Zeng, Yiping; Williams, Elizabeth D.; Rescigno, María; Cavallaro, Ugo

doi:10.1083/jcb1846oia14

Cited by 18 publications

(27 citation statements)

References 35 publications

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“…Subsequent work has shown overexpression of L1CAM in a variety of human tumours, in which it is associated with bad prognosis and metastases formation (Thies et al, 2002;Fogel et al, 2003a, b;Boo et al, 2007;Kaifi et al, 2007). Furthermore, L1CAM was detected in tumour-associated endothelium (Issa et al, 2009;Maddaluno et al, 2009). Expression of L1CAM was also described in pancreatic ductal adenocarcinomas (PDACs) (Sebens Muerkoster et al, 2007Geismann et al, 2009).…”

Section: Introductionmentioning

confidence: 97%

L1CAM–integrin interaction induces constitutive NF-κB activation in pancreatic adenocarcinoma cells by enhancing IL-1β expression

et al. 2010

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L1 cell adhesion molecule (L1CAM) overexpression is often associated with bad prognosis in various human carcinomas. Recent studies also suggest a role of L1CAM in pancreatic ductal adenocarcinomas (PDAC). To further address its contribution, we expressed functional domains of L1CAM in PT45-P1 PDAC cells. We found that L1CAM that is full length (L1-FL), but neither the soluble ectodomain (L1ecto) nor the cytoplasmic part (L1cyt), could enhance cell proliferation or tumour growth in mice. Expression of L1-FL resulted in constitutive activation of NF-jB, which was abolished by L1CAM knockdown. We showed that the expression of IL-1b was selectively upregulated by L1-FL, and increased IL-1b levels were instrumental for sustained NF-jB activation. IL-1b production and NF-jB activation were abolished by knockdown of a5-integrin and integrin-linked kinase, but insensitive to depletion of L1CAM cleavage proteinases. Supporting these data, PT45-P1 cells transduced with an L1CAM mutant deficient in integrin binding (L1-RGE) did not support the described L1-FL functions. Our results suggest that membranous L1CAM interacts with RGD-binding integrins, leading to sustained NF-jB activation by IL-1b production and autocrine/paracrine signalling. The unravelling of this novel mechanism sheds new light on the important role of L1CAM expression in PDAC cells.

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Section: Introductionmentioning

confidence: 97%

L1CAM–integrin interaction induces constitutive NF-κB activation in pancreatic adenocarcinoma cells by enhancing IL-1β expression

et al. 2010

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“…endothelial-specific ablation of L1 in mice was achieved by crossing Tie2-Cre with L1 floxed mice (10). Indeed, L1 was readily detectable in the tumor vessels of control, L1 floxed mice, while no L1 immunoreactivity was observed in the vasculature of Tie2-Cre;L1 floxed tumors ( Figure 1A).…”

Section: Introductionmentioning

confidence: 99%

Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization

Magrini¹,

Villa²,

Angiolini³

et al. 2014

J. Clin. Invest.

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Besides the nervous system, L1 is expressed in many human cancers, including ovarian and endometrial carcinoma, pancreatic ductal adenocarcinoma (PDAC), melanoma and glioblastoma. L1 expression confers motile and invasive properties to tumor cells, supporting cancer growth, metastasis, and chemoresistance and often acting as a marker of poor prognosis (8). L1 has also been detected in the hematopoietic system, in particular in immune cells of myelomonocytic and lymphoid origin (9), and we have previously reported L1-dependent transmigration of dendritic cells across the endothelium (10).An intriguing aspect of L1 biology is its expression in the vascular system: while no or very little L1 is detectable in the vasculature of most normal tissues, its level is markedly increased in the vasing the mechanisms of pathological angiogenesis and to identifying novel cancer vessel-specific markers.L1 (also known as L1CAM or CD171) is a transmembrane glycoprotein belonging to the immunoglobulin superfamily and is composed of an extracellular portion, containing 6 Ig-like domains and 5 fibronectin type III repeats, followed by a transmembrane region, and a highly conserved cytoplasmic tail (5). L1 was discovered and characterized as a cell-adhesion molecule in the nervous system (6), where it is involved in neurite outgrowth and fasciculation as well as cell adhesion and migration. In addition to homophilic binding, L1 can establish cis-or trans-interactions with different binding partners, such as integrins, CD24, neurocan, neuropilin-1, and other members of the neural cell adhesion family (7).

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“…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.…”

Section: Introductionmentioning

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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The adhesion molecule L1 regulates transendothelial migration and trafficking of dendritic cells

Cited by 18 publications

References 35 publications

L1CAM–integrin interaction induces constitutive NF-κB activation in pancreatic adenocarcinoma cells by enhancing IL-1β expression

L1CAM–integrin interaction induces constitutive NF-κB activation in pancreatic adenocarcinoma cells by enhancing IL-1β expression

Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization

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

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