Soluble SEMA4D/CD100: A novel immunoregulator in infectious and inflammatory diseases

Maleki, Kimia T.; Cornillet, Martin; Björkström, Niklas K.

doi:10.1016/j.clim.2015.12.012

Cited by 59 publications

(50 citation statements)

References 76 publications

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“…Sema4D-deficient mice exhibited functional defects in the immune system [3]. 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].…”

Section: Introductionmentioning

confidence: 99%

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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: 99%

“…Sema4D/CD100 (semaphorin 4D) belongs to the class 4 semaphorin, which is involved in the regulation of the immune system [3][4][5]. Sema4D-deficient mice exhibited functional defects in the immune system [3].…”

Section: Introductionmentioning

confidence: 99%

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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“…1C and Table S2), confirming that specific sets of proteins were released by stimulation with the STING agonist. Among the 23 identified proteins, SEMA4D has been well-characterized as a proinflammatory protein (26). Notably, the number of peptide spectrum matches of SEMA4D was relatively high among them ( Table 1), suggesting that SEMA4D is an abundant protein in the culture supernatant of STING-activated cells.…”

Section: Identification Of Sema4d As a Novel Protein Released By Stinmentioning

confidence: 99%

Activation of stimulator of interferon genes (STING) induces ADAM17-mediated shedding of the immune semaphorin SEMA4D

Motani

Kosako

2018

Journal of Biological Chemistry

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Stimulator of interferon genes (STING) is an endoplasmic reticulum-resident membrane protein that mediates cytosolic pathogen DNA-induced innate immunity and inflammatory responses in host defenses. STING is activated by cyclic di-nucleotides and is then translocated to the Golgi apparatus, an event that triggers STING assembly with the downstream enzyme TANK-binding kinase 1 (TBK1). This assembly leads to the phosphorylation of the transcription factor interferon regulatory factor 3 (IRF3), which in turn induces expression of type-I interferon (IFN) and chemokine genes. STING also mediates inflammatory responses independently of IRF3, but these molecular pathways are largely unexplored. Here, we analyzed the RAW264.7 macrophage secretome to comprehensively identify proinflammatory factors released into the extracellular medium upon STING activation. In total, we identified 1299 proteins in macrophage culture supernatants, of which 23 were significantly increased after STING activation. These proteins included IRF3-dependent cytokines, as well as previously unknown targets of STING, such as the immune semaphorin SEMA4D/CD100, which possesses proinflammatory cytokine-like activities. Unlike for canonical cytokines, the expression of the SEMA4D gene was not up-regulated. Instead, upon STING activation, membrane-bound SEMA4D was cleaved into a soluble form, suggesting the presence of a post-translational shedding machinery. Importantly, the SEMA4D shedding was blocked by TMI-1, an inhibitor of the sheddase ADAM metallopeptidase domain 17 (ADAM17) but not by the TBK1 inhibitor BX795. These results suggest that STING activates ADAM17 and that this activation produces soluble proinflammatory SEMA4D independently of the TBK1/IRF3-mediated transcriptional pathway.

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“…Mean haemoglobin A 1 C of the diabetic patients was 7.5 (±1.8 SD, range 5. [4][5][6][7][8][9][10][11]. Most prevalent valvular heart disease was tricuspid regurgitation, followed by mitral regurgitation (33.3% and 27.7%, respectively).…”

Section: Study Population-demographics and Comorbiditiesmentioning

confidence: 99%

Semaphorin 4D levels in heart failure patients: a potential novel biomarker of acute heart failure?

et al. 2018

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AimsSemaphorin 4D (Sema4D) is expressed on platelets and T‐cells and known to be involved in inflammation. The aims of this study include comparing Sema4D and N terminal pro brain natriuretic peptide (NT‐proBNP) serum levels in heart failure (HF) patients to a control group, evaluating the correlation between Sema4D and NT‐proBNP levels, and assessing Sema4D serum levels in HF patients during acute exacerbation and remission.Methods and resultsForty‐five patients diagnosed with HF (based on echocardiographic findings, positive NT‐proBNP levels, and normal C‐reactive protein) and 11 healthy controls (declaring no chronic diseases or medications) comprised the study population. Demographic, clinical, laboratory, and echocardiographic data were used to create the study database. NT‐proBNP and Sema4D serum samples were taken on admission and discharge. NT‐proBNP levels were significantly higher in the HF group than in controls (P < 0.001). Sema4D levels were significantly higher in HF patients than in healthy controls (2143.04 ± 1253 vs. 762.18 ± 581.6 ng/mL, P < 0.001, respectively). Using linear regression, a higher creatinine level was found to predict both higher levels of NT‐proBNP and Sema4D (P = 0.05 and P < 0.014, respectively), while a reduced ejection fraction was found to predict higher NT‐proBNP levels only (P < 0.001 and P = 0.87, respectively). Average Sema4D levels reduced significantly at remission (3534.94 ± 1650.55 vs. 2455.67 ± 1424, P = 0.03), while mean NT‐proBNP levels did not change significantly.ConclusionsSema4D levels in HF patients' serum are significantly higher than in healthy controls. Clinical improvement caused rapid reduction in Sema4D levels, possibly reflecting the inflammatory aspect of HF. These findings might suggest that Sema4D can be used as a diagnostic biomarker of acute HF. Further studies of Sema4D and HF are warranted.

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Soluble SEMA4D/CD100: A novel immunoregulator in infectious and inflammatory diseases

Cited by 59 publications

References 76 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

Activation of stimulator of interferon genes (STING) induces ADAM17-mediated shedding of the immune semaphorin SEMA4D

Semaphorin 4D levels in heart failure patients: a potential novel biomarker of acute heart failure?

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