The Neurorepellent Slit2 Inhibits Postadhesion Stabilization of Monocytes Tethered to Vascular Endothelial Cells

Mukovozov, Ilya; Huang, Yiwei; Zhang, Qiuwang; Liu, Guang Ying; Siu, Allan; Sokolskyy, Yaroslav; Patel, Sajedabanu; Hyduk, Sharon J.; Kutryk, Michael J.B.; Cybulsky, Myron I.; Robinson, Lisa A.

doi:10.4049/jimmunol.1500640

Cited by 20 publications

(26 citation statements)

References 52 publications

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“…Secreted Slit2 interacts with Robo on the surface of vascular smooth muscle cells and monocytes, in order to inhibit migration of these cells toward diverse inflammatory chemoattractant cues in vitro and in vivo (12–14). Administration of Slit2 to atherosclerosis-prone low-density lipoprotein (LDL) receptor-deficient mice was able to inhibited monocyte recruitment to nascent atherosclerotic lesions, which supports a role for Slit2 in preventing early vascular inflammation (15). It is well known that endothelial dysfunction is a key step in the initiation of cardiovascular diseases, and endothelial cell proliferation, migration and tube formation are critical for neovascularization and angiogenesis.…”

Section: Introductionmentioning

confidence: 83%

Slit2 suppresses endothelial cell proliferation and migration by inhibiting the VEGF-Notch signaling pathway

Yang

et al. 2017

Molecular Medicine Reports

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Slit homolog 2 (Slit2) is distributed in various tissues and participates in numerous cellular processes; however, the role of Slit2 in the regulation of angiogenesis remains controversial, since it has previously been reported to exert proangiogenic and antiangiogenic activities. The present study aimed to investigate the effects of Slit2 on vascular endothelial cell proliferation and migration in vitro, and to reveal the possible underlying signaling pathway. Aortic endothelial cells were isolated from Sprague Dawley rats and cultured. Cell proliferation assay, cell migration assay, immunocytochemistry and small interfering RNA transfection were subsequently performed. The results demonstrated that exogenous Slit2 administration markedly suppressed TNF-α-induced endothelial cell proliferation and migration in vitro. In addition, TNF-α application upregulated the protein expression levels of vascular endothelial growth factor (VEGF) and Notch in RAECs, whereas Slit2 administration downregulated VEGF and Notch expression in RAECs cultured in TNF-α conditioned medium. Further studies indicated that knockdown of VEGF suppressed the effects of TNF-α on the induction of RAEC proliferation and migration. VEGF knockdown-induced inhibition of RAEC proliferation and migration in TNF-α conditioned medium was also achieved without Slit2 administration. Furthermore, VEGF knockdown markedly decreased Notch1 and Notch2 expression. These results indicated that Slit2 suppresses TNF-α-induced vascular endothelial cell proliferation and migration in vitro by inhibiting the VEGF-Notch signaling pathway. Therefore, Slit2 may inhibit the proliferation and migration of endothelial cells during vascular development.

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Section: Introductionmentioning

confidence: 83%

Slit2 suppresses endothelial cell proliferation and migration by inhibiting the VEGF-Notch signaling pathway

Yang

et al. 2017

Molecular Medicine Reports

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“…Our data showed a temporospatial relationship between expression of CAMs / MCP-1 and recruitment of inflammatory cells, and vascular expression of Slit/Robo, suggesting that antichemotactic molecules may be involved in halting the adventitial entry and trafficking of leukocytes. In agreement with this concept, systemic administration of Slit2 has been shown to reduce monocyte recruitment to atherosclerotic lesions in LDL receptor-deficient mice 27 and macrophage infiltration in rats with crescent glomerulonephritis. 28 Moreover, Slit2 administration to mice that underwent renal ischemia reperfusion injury resulted in inhibition of neutrophil and macrophage infiltration.…”

Section: Discussionmentioning

confidence: 55%

“…27 At day 1 postinjury, when the highest levels of Slit/Robo were observed, ICAM-1 expression had already decreased by 50%, whereas the number of adventitial neutrophils was reduced by more than 75%. Our data showed a temporospatial relationship between expression of CAMs / MCP-1 and recruitment of inflammatory cells, and vascular expression of Slit/Robo, suggesting that antichemotactic molecules may be involved in halting the adventitial entry and trafficking of leukocytes.…”

Section: Discussionmentioning

confidence: 92%

“…The unique properties of Slit2 to selectively avert migration of leukocyte subpopulations to injured tissues, and its ability to impair platelet adhesion and spreading, places this molecule not only as a key regulator of vascular function but also as a novel therapeutic tool to prevent inflammation-driven vascular and renal injury. 27, 40, 41 …”

Section: Discussionmentioning

confidence: 99%

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Potential Role of Axonal Chemorepellent Slit2 in Modulating Adventitial Inflammation in a Rat Carotid Artery Balloon Injury Model

Liu

Yan

Subramanian³

et al. 2016

Journal of Cardiovascular Pharmacology

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Leukocyte infiltration of adventitial and perivascular tissues is an early event in the development of vascular remodeling after injury. We investigated whether Slit/Robo—an axonal chemorepellent system in vertebrate and invertebrate development—is activated during the inflammatory phase that follows endothelial denudation. Using the rat carotid artery model of angioplasty, we conducted a time course analysis of mRNAs encoding Slit ligands (Slit2 and Slit3) and Robo receptors (Robo1, Robo2 and Robo4), as well as proinflammatory cell adhesion molecule (CAM) genes. Adventitial inflammatory cells were counted in immunostained arterial sections. E-selectin, vascular CAM-1 (VCAM-1), and intercellular CAM-1 (ICAM-1) were upregulated 2–3 hr after injury, followed by infiltration of neutrophils and monocytes as evidenced by real-time PCR, in situ hybridization, and immunohistochemistry. Slit2, Slit3, and Robo genes exhibited no expression changes at 3 hr; however, they were markedly upregulated 1 day after angioplasty. ICAM-1 expression was reduced by 50%, and the number of adventitial neutrophils decreased by >75% one day after angioplasty. Slit2 has been shown to be a potent chemorepelent of leukocytes, endothelial cells and smooth muscle cells. Thus, we decided to further investigate the localization of Slit2 in injured vessels. Immunohistochemical stainings revealed the presence of Slit2 within the vessel wall and in the perivascular vasa vasorum of naive and injured arteries. Double immunohistochemical analyses showed that infiltrating monocytes expressed Slit2 in the perivascular and adventitial tissues of injured arteries 1 and 3 days postangioplasty. In addition, recombinant full-length Slit2 and Slit2-N/1118, an N-terminal fragment of Slit2, inhibited stromal cell-derived factor 1 (SDF-1)-mediated migration of circulating rat peripheral blood mononuclear cells. In summary, adventitial activation of CAM genes and neutrophil infiltration preceded upregulation of Slit/Robo genes. Sli2 expression colocalized with infiltrating inflammatory cells in the adventitial layer. This temporospatial association suggests that leukocyte chemorepellent Slit2 may be involved in halting the adventitial accumulation of inflammatory cells in injured vessels.

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“…3). Interestingly, mCD40L not only upregulated genes enhancing immunostimulatory function but also downregulated those negatively impacting this process, such as SLIT2, which is involved in inhibition of chemotaxis and adhesion of monocytes to activated human endothelial cells and to immobilized ICAM-1 and VCAM-1 cells 24 .…”

Section: Discussionmentioning

confidence: 99%

CD40L membrane retention enhances the immunostimulatory effects of CD40 ligation

Elmetwali

Salman

Wei

et al. 2020

Sci Rep

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In carcinomas, the nature of CD40 ligand shapes the outcome of CD40 ligation. To date, the consequences of membrane-bound CD40L (mCD40L) on its immune-stimulatory function are unknown. Here, we examined the impact of mCD40L versus soluble CD40L (sCD40L) on T24 bladder carcinoma gene expression profiling. Of 410 differentially expressed genes, 286 were upregulated and 124 downregulated by mCD40L versus sCD40L. Gene ontology enrichment analysis revealed immunestimulatory function as the most significant enriched biological process affected by upregulated transcripts, while those downregulated were critical for cell growth and division. Furthermore, immature dendritic cells (iDC) responded to mCD40L with enhanced maturation and activation over sCD40L evidenced by higher expression levels of CD83, CD86, HLA-DR and CD54, increased secretion of IL12 and IL10 and higher tumour-antigen (TA) uptake capacity. Furthermore, autologus CD3+ T cells responded to TA-loaded mCD40L-activated DC with increased proliferation and cytotoxic response (CD107a and IFN-γ-producing CD3+ CD8+ T cells) to the tumour-loaded autologous PBMCs compared to sCD40L. Thus, these data indicate that mCD40L enhances the immunostimulatory capacity over sCD40L. Furthermore, the ability of mCD40L to also directly induce cell death in CD40-expressing carcinomas, subsequently releasing tumour-specific antigens into the tumour microenvironment highlights the potential for mCD40L as a multi-faceted anti-cancer immunotherapeutic. The fundamental role of the CD40 receptor, a member of the TNFR superfamily together with its ligand (CD40L/ CD154) in coordinating immune responses has been widely recognised as an early event in initiating immune responses 1. CD40, a 40-kD type 1 transmembrane protein is expressed in normal B cells, malignant hematopoietic cells and antigen presenting cells (APC), including dendritic cells (DC) and monocytes 2,3. Furthermore, activated CD4 + and CD8+ T cells also express CD40 receptor, where in absence of CD40 expression, CD8+ T cells were unable to differentiate into memory cells or receive CD4 help 4. In addition to hematopoietic cells, several carcinomas express CD40 receptor, including those of the ovary, liver, and bladder, despite receptor expression being undetectable in normal epithelium derived from the same tissue 5. In contrast to the wide-spectrum of CD40 expression, the expression of CD40L, a 32-kD protein is restricted mainly to activated CD4+ T cells and, to a lesser extent, activated B cells and platelets 6. In hematopoietic cells the importance of CD40-CD40L interaction is well-recognized particularly in shaping adaptive immune responses, where the outcome of CD40 ligation is cell-type dependant, with CD40 activation in DC leading to differentiation into IL12-and IFNγ-secreting cells and upregulation of co-stimulatory and adhesion molecules; while B cells respond by Ig-class switching 7. Furthermore, the strength of CD40 ligation by CD40L can influence the signalling outcome, with strong CD40 ligation enhancing anti...

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The Neurorepellent Slit2 Inhibits Postadhesion Stabilization of Monocytes Tethered to Vascular Endothelial Cells

Cited by 20 publications

References 52 publications

Slit2 suppresses endothelial cell proliferation and migration by inhibiting the VEGF-Notch signaling pathway

Slit2 suppresses endothelial cell proliferation and migration by inhibiting the VEGF-Notch signaling pathway

Potential Role of Axonal Chemorepellent Slit2 in Modulating Adventitial Inflammation in a Rat Carotid Artery Balloon Injury Model

CD40L membrane retention enhances the immunostimulatory effects of CD40 ligation

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