The role of Sema4D/CD100 as a therapeutic target for tumor microenvironments and for autoimmune, neuroimmune and bone diseases

Wu, Mingfu; Li, Jing; Gao, Qinglei; Ye, Fei

doi:10.1517/14728222.2016.1139083

Cited by 27 publications

(22 citation statements)

References 94 publications

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“…Previous studies found that Sema4D was upregulated in autoimmune diseases and it plays key roles in regulating innate and adaptive immune responses [4,6,7]. In addition, Sema4D was found highly and selectively produced by the osteoclasts in bone [8]. It suppressed the differentiation of osteoblast, whereas it did not affect osteoclastogenesis [9].…”

Section: Introductionmentioning

confidence: 96%

Sema4D Aggravated LPS-Induced Injury via Activation of the MAPK Signaling Pathway in ATDC5 Chondrocytes

Lei

Zhuang

et al. 2020

BioMed Research International

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Osteoarthritis (OA) is the most common chronic degenerative joint disease, and it remains the main cause of chronic disability in elderly individuals. Sema4D (semaphorin 4D) is involved in the immune system and related to bone injury, osteoporosis, osteoblast differentiation, and rheumatoid arthritis. However, the role of Sema4D in OA remains unclear. Hence, the LPS-stimulated chondrocyte cell injury model was constructed in this study to investigate the role of Sema4D in OA development. The results showed that Sema4D was increased in LPS-treated ATDC5 cells, and the knockdown of Sema4D suppressed the decline of cell viability, the increase of cell apoptosis, and the increase of IL-6, IL-1β, and TNF-α secretion in ATDC5 cells induced by LPS. Meanwhile, Sema4D overexpression aggravated the cell injury triggered by LPS, and inhibiting Plexin B1 partly abolished the effect of Sema4D overexpression on LPS-induced chondrocyte injury. Furthermore, silencing of Sema4D blocked the activation of the MAPK pathway in LPS-stimulated ATDC5 cells. Enhanced Sema4D promoted the activation of the MAPK pathway in LPS-stimulated ATDC5 cells. What is more, inhibiting the MAPK signaling pathway abolished the promoting effect of Sema4D overexpression on LPS-induced chondrocyte injury. Therefore, our study suggested that the knockdown of Sema4D protects ATDC5 cells against LPS-induced injury through inactivation of the MAPK signaling pathway via interacting with Plexin B1.

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Section: Introductionmentioning

confidence: 96%

Sema4D Aggravated LPS-Induced Injury via Activation of the MAPK Signaling Pathway in ATDC5 Chondrocytes

Lei

Zhuang

et al. 2020

BioMed Research International

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“…Previous reports suggested that soluble Sema4D exerts multiple effects on CD4+ T cells in several diseases [29,30], so we speculated that Sema4D may also have effects on CD4+ T cells in AS patients. CD4+ T cells were harvested from PBMCs derived from AS patients and healthy donors, stained with CFSE, then co-cultured with or without soluble human Sema4D-Fc in the presence of anti-Sema4D or isotype control.…”

Section: Treg Cell Differentiationmentioning

confidence: 87%

“…Accumulating evidence has showed that the aryl hydrocarbon receptor (AhR) [9,10] [29][30][31]. It has been demonstrated that AhR activation by its high-affinity ligand 6 formylindolo[3,2-b]carbazole (FICZ) may induce Th17 cells and promote IL-17 production [11].…”

mentioning

confidence: 99%

Semaphorin 4D induces an imbalance of Th17/Treg cells by activating the aryl hydrocarbon receptor in ankylosing spodylitis

Xie

Zitao

2020

Preprint

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Background: Semaphorin 4D (Sema4D) is constitutively expressed on T cells and osteoclasts, and regulates T cell proliferation and bone remodeling. In addition, several studies have shown that Sema4D is involved in the pathogenesis of autoimmunity. We undertook this study to investigate the mechanism by which Sema4D affects the pathogenic progress of ankylosing spondylitis (AS). Methods: Soluble Sema4D (sSema4D) levels in serum were analyzed by enzyme-linked immunosorbent assay. The cell surface levels and transcripts of Sema4D were evaluated in CD4+ and CD19+ cells from the AS patients and healthy individuals. The mRNA expression levels were assessed by quantitative polymerase chain reaction (qPCR). The proportions of Treg cells and IL-17-producing T-cells (Th17 cells) differentiated from CD4+ T cells were analyzed by flow cytometric analysis. The aryl hydrocarbon receptor (AhR) agonistic effect of Sema4D was detected by analyzing the activation of downstream signaling pathways and target genes using Luciferase and EROD assay. Results: Levels of sSema4D were elevated in both serum from AS patients, and clinical features markers were correlated with serum sSema4D levels. Sema4D facilitated CD4+ T cells proliferation and Th17 cells differentiation and inhibited Treg cells differentiation by enhancing RORγt expression and reducing Foxp3 expression, with increasing expression and secretion of IL-17 and IL-22. It induced the expression and activity of AhR target gene CYP1A1 and XRE reporter activity via interaction with CD72. Conclusions: These findings indicate that Sema4D as a potent activator of T cells in the immune response contributes to the inflammation of AS by inducing imbalance in Th17 and Treg cell populations in an AhR-dependent manner, suggesting it is a crucial participant in AS pathogenesis. Background Ankylosing Spondylitis(AS) is a chronic auto-inflammatory rheumatic disease characterized by immuno-inflammatory responses and abnormal bone remodeling, such as inflammatory cytokines, syndesmophytes, erosions and osteoporosis, are features of progressive ankylosing spondylitis[1, 2].Accumulating findings demonstrated that T-helper 17 (Th17) cells as a subgroup of CD4 + T cells, secrete interleukin (IL)-17, enhance pro-inflammatory effects and aggravate AS. Conversely,

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“…It is hypothesized that antibody neutralization of CD100 inhibits cancer progression by disrupting the CD100–PLXNB1 interaction in tumor tissues and enhancing recruitment of activated monocytes and lymphocytes into the tumor (9, 10, 30, 31). However, if the expansion capacity of the recruited immune cells is inhibited at the same time, the antitumor response will be weakened.…”

Section: Discussionmentioning

confidence: 99%

Intact CD100–CD72 Interaction Necessary for TCR-Induced T Cell Proliferation

2017

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Targeting CD100 by antibody blockade is a potential therapeutic strategy for cancers, but the functional effects on T cells following blockade of this immune activating molecule are rarely considered. Indeed, CD100 is highly expressed in T cells and anti-CD100 antibodies play a role during T cell proliferation; however, the outcome varies from different studies and the underlying mechanism is still unclear. To address this, monoclonal antibody clones directed against CD100 were evaluated. In their soluble form, four of these antibodies significantly reduced the expansion of T cells in the presence of bead-bound anti-CD3/CD28, either in total peripheral blood mononuclear cell or purified T cell culture systems. Similar inhibition was seen when blocking CD100–CD72 interaction by soluble anti-CD72 instead of anti-CD100 antibodies. Conversely, restoring the interaction by CD72-Fc eliminated the soluble anti-CD100-induced inhibitory effect. Taken together, these results reveal that T cell proliferation is regulated by CD100 via interaction with CD72. They further establish an in vitro system to evaluate the inhibitory effect of anti-CD100 antibodies on T cells, to which attention should be paid in clinical trials in order to avoid potential side effects.

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The role of Sema4D/CD100 as a therapeutic target for tumor microenvironments and for autoimmune, neuroimmune and bone diseases

Cited by 27 publications

References 94 publications

Sema4D Aggravated LPS-Induced Injury via Activation of the MAPK Signaling Pathway in ATDC5 Chondrocytes

Sema4D Aggravated LPS-Induced Injury via Activation of the MAPK Signaling Pathway in ATDC5 Chondrocytes

Semaphorin 4D induces an imbalance of Th17/Treg cells by activating the aryl hydrocarbon receptor in ankylosing spodylitis

Intact CD100–CD72 Interaction Necessary for TCR-Induced T Cell Proliferation

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