RGC-32 Promotes Th17 Cell Differentiation and Enhances Experimental Autoimmune Encephalomyelitis

Rus, Violeta; Nguyen, Vinh; Tatomir, Alexandru; Lees, Jason R.; Mekala, Armugam P.; Boodhoo, Dallas; Tegla, Cosmin; Luzina, Irina G.; Antony, Paul A.; Cudrici, Cornelia; Badea, Tudor C.; Rus, Horea

doi:10.4049/jimmunol.1602158

Cited by 15 publications

(23 citation statements)

References 55 publications

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“…As previously reported, RGC-32 −/− mice developed significantly less severe disease at the stage of peak disease [7] (Fig. 11a).…”

Section: Resultssupporting

confidence: 85%

“…RGC-32 KO and WT female mice (8–10 weeks old) were injected subcutaneously in two locations in the dorsal flank with an emulsion containing 200 μg of MOG 35–55 (Anaspec, Fremont, CA) and complete Freund’s adjuvant (CFA) (Difco, Detroit, MI) as previously described [7, 15]. Pertussis toxin (400 ng; List Biological Laboratories, Campbell, CA) was administered intraperitoneally on days 0 and 2.…”

Section: Methodsmentioning

confidence: 99%

“…Pertussis toxin (400 ng; List Biological Laboratories, Campbell, CA) was administered intraperitoneally on days 0 and 2. Mice were monitored daily, and the disease was scored on a scale of 0–5 as follows: 1, limp tail; 2, hindlimb paresis; 3, hindlimb paralysis; 4, tetraplegia; 5, moribund [7, 15]. All procedures were approved by the University of Maryland School of Medicine Office of Animal Welfare Assurance.…”

Section: Methodsmentioning

confidence: 99%

“…RGC-32 −/− mice have normal Th1, Th2, and regulatory T-cell differentiation but show defective Th17 differentiation in vitro. This impaired Th17 differentiation is associated with defects in IFN regulatory factor 4, B cell–activating transcription factor, retinoic acid–related orphan receptor γt, and SMAD2 activation [7]. In vivo, RGC-32 −/− mice display an attenuated experimental autoimmune encephalomyelitis (EAE) phenotype, accompanied by decreased CNS inflammation and a reduced frequency of IL-17- and GMCSF-producing CD4 + T cells.…”

Section: Introductionmentioning

confidence: 99%

“…In vivo, RGC-32 −/− mice display an attenuated experimental autoimmune encephalomyelitis (EAE) phenotype, accompanied by decreased CNS inflammation and a reduced frequency of IL-17- and GMCSF-producing CD4 + T cells. These studies have identified RGC-32 as a novel regulator of Th17 cell differentiation in vitro and in vivo and suggest that RGC-32 is a potential therapeutic target in multiple sclerosis [7]. Since RGC-32 is also expressed by astrocytes in MS lesions, its role in these cells needs to be explored.…”

Section: Introductionmentioning

confidence: 99%

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RGC-32 regulates reactive astrocytosis and extracellular matrix deposition in experimental autoimmune encephalomyelitis

et al. 2018

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Extracellular matrix (ECM) deposition in active demyelinating multiple sclerosis (MS) lesions may impede axonal regeneration and can modify immune reactions. Response gene to complement (RGC)-32 plays an important role in the mediation of TGF-β downstream effects, but its role in gliosis has not been investigated. To gain more insight into the role played by RGC-32 in gliosis, we investigated its involvement in TGF-β-induced ECM expression and the upregulation of the reactive astrocyte markers α-smooth muscle actin (α-SMA) and nestin. In cultured neonatal rat astrocytes, collagens I, IV, and V, fibronectin, α-SMA, and nestin were significantly induced by TGF-β stimulation, and RGC-32 silencing resulted in a significant reduction in their expression. Using astrocytes isolated from RGC-32 knock-out (KO) mice, we found that the expression of TGF-β-induced collagens I, IV, and V, fibronectin, and α-SMA was significantly reduced in RGC-32 KO mice when compared with wild-type (WT) mice. SIS3 inhibition of Smad3 phosphorylation was also associated with a significant reduction in RGC-32 nuclear translocation and TGF-β-induced collagen I expression. In addition, during experimental autoimmune encephalomyelitis (EAE), RGC-32 KO mouse astrocytes displayed an elongated, bipolar phenotype, resembling immature astrocytes and glial progenitors whereas those from WT mice had a reactive, hypertrophied phenotype. Taken together, our data demonstrate that RGC-32 plays an important role in mediating TGF-β-induced reactive astrogliosis in EAE. Therefore, RGC-32 may represent a new target for therapeutic intervention in MS.

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“…As previously reported, RGC-32 −/− mice developed significantly less severe disease at the stage of peak disease [7] (Fig. 11a).…”

Section: Resultssupporting

confidence: 85%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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RGC-32 regulates reactive astrocytosis and extracellular matrix deposition in experimental autoimmune encephalomyelitis

et al. 2018

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Oncogenic gene RGC‐32 is a direct target of miR‐26b and facilitates tongue squamous cell carcinoma aggressiveness through EMT and PI3K/AKT signalling

Yang

Chen

et al. 2020

Cell Biochemistry & Function

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Growing data have recognized the significance of Response Gene to Complement (RGC)-32 in numerous tumour developments. Notwithstanding, the functional role and underlying mechanism of it in tongue squamous cell carcinoma (TSCC) remain enigmatic. Here, to identify the impact of RGC-32 in TSCC, its expression in multiple TSCC cells was measured and loss-of-function experiments in cell lines were performed to illuminate the function of it induced TSCC progression, via si-RNA knockdown, CCK-8, colony formation, wound-healing, transwell, flow cytometry and western blot assays. To clarify potential mechanism, expressions of hallmarks in epithelial-mesenchymal transition (EMT) process and PI3K/AKT signalling were assessed, and the upstream miR regulator of RGC-32 was predicted and verified by applying bioinformatic approaches and dual-luciferase reporter assay, respectively. Finally, the rescue experiments were applied to better elucidate the effect of miR-26b/RGC-32 axis in TSCC behaviours. As a result, RGC-32 was upregulated in TSCC cells and knocking down of it abrogated cell proliferation, trans-migration and invasion, whilst promoted apoptosis in TSCC, which was regulated through repressing EMT and inactivation of PI3K/AKT signalling. Subsequently, miR-26b was predicted and identified as an upstream regulator of RGC-32, and the pro-tumorigenic effect of RGC-32 was reversed by miR-26b overexpression. Collectively, our results demonstrated that RGC-32 facilitated TSCC progression, which was modulated by activations of PI3K/AKT pathway and EMT process, and reduction of its negative regulator of miR-26b. These findings highlight a novel role of miR-26b/RGC-32 axis in TSCC and underlying mechanism, encouraging a potent usage in TSCC treatment. Significance of the study: We first uncovered that Response Gene to Complement-32 played a significantly pro-tumorigenic role in tongue squamous cell carcinoma (TSCC), which was closely regulated by downregulation of miR-26b and activations of epithelial-mesenchymal transition process and PI3K/AKT signalling. These findings contribute to better understand the molecular mechanism in carcinogenesis of TSCC, and shed some light on promising strategy for TSCC therapeutics.

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RGC-32 and diseases: the first 20 years

et al. 2019

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RGC-32 Promotes Th17 Cell Differentiation and Enhances Experimental Autoimmune Encephalomyelitis

Cited by 15 publications

References 55 publications

RGC-32 regulates reactive astrocytosis and extracellular matrix deposition in experimental autoimmune encephalomyelitis

RGC-32 regulates reactive astrocytosis and extracellular matrix deposition in experimental autoimmune encephalomyelitis

Oncogenic gene RGC‐32 is a direct target of miR‐26b and facilitates tongue squamous cell carcinoma aggressiveness through EMT and PI3K/AKT signalling

RGC-32 and diseases: the first 20 years

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