Metformin attenuates bleomycin-induced scleroderma by regulating the balance of Treg/Teff cells and reducing spleen germinal center formation

Wang, Yanlin; Zhang, Shulan; Liang, Zheng; Feng, Min; Zhao, Xiangcong; Qin, Kaili; Gao, Chong; Li, Xiaofeng; Guo, Hui; Luo, Jing

doi:10.1016/j.molimm.2019.07.002

Cited by 23 publications

(14 citation statements)

References 29 publications

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“…The treated group with metformin, showed reduction of Bcl2 expession in all zones. In agreement with our finding, it was reported the metformin treatment inhibited spleen germinal center B cells formation in mice, which in turn reduce Bcl2 expression [21]. Also, it was documented that metformin could down-regulate the expression of anti-apoptotic protein Bcl2 expression in the synovial fluid of collagen induced arthritis rat model [22].…”

Section: Discussionsupporting

confidence: 91%

Protective Role of Ginger against Metformin Induced Alteration in Bcl2 Expression in the Spleen of Normoglycemic Albino Rat

Hashish¹

2019

J Histol Histopathol

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Background: The spleen is the largest and most essential organ in lymphoid system for the immunological reactions in the blood. Apoptosis can be defined as a programmed cell death in tissues. The B-cell leukemia/lymphoma-2 (Bcl-2) families are apoptosis regulators. Metformin is a safe drug that can lower blood glucose level, and may be used in non-diabetic patients with polycystic ovarian syndromeor with impaired glucose tolerance. Ginger is a member of ginger family. It has been used in India as a treatment for headache and common cold. It is known as an anti-oxidant agent. Aim of the work: This study has been designed to evaluate the possible pathological effect of metformin on spleen in normoglycemic rats, it's possible effect on Bcl2 expression, and the potential protective role of ginger. Material and methods: Thirty adult male albino rats (200-250gm) were obtained from AL-Nile Experimental Animal Center, Mansoura, Egypt. The animals were divided randomly into 3groups 10 rats each; Control, metformin treated group (200mg/kg orally for 1 month), and metformin-ginger group (200mg/kg /day metformin + 300 mg/kg/day ginger for 1 month). Rats in each group were weighted and sacrificed at the end of the experiment, spleen were dissected. The specimens were used for paraffin sections, stained with hematoxylin-eosin (HE), Masson's trichrome and Bcl2 immunohistochemistry. Results: Sections of ME treated group showed distorted splenic contour, degenerated cells with vacuolated cytoplasm and pyknoticnuclei. Masson trichrome stained sections revealed massive fibrosis in white pulp, red pulp and among cellular cords. The spleen treated with (ME+G) showed normal architecture without distortion, well defined white pulp, red pulp and splenic sinuses. The cellular cord showed lymphocytes and macrophages. Masson trichrome stained sections of the spleen showed minimal fibrosis among cellular cords. The treated group with metformin (ME), showed reduction of Bcl2 expression in all zones. While, the metformin-ginger (ME+G) treated group showed extensive expression in germinal center, mantle layer and marginal zone. Conclusion: From this study, it be concluded that metformin like any other drug may have beneficial curative properties in some medical conditions, however it should used be with caution to avoid its hazardous effect especially in the spleen which is the most vital organ in lymphatic and immune system. Also, ginger is a natural herbal agent could protect from hazardous side effect of metformin.

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Section: Discussionsupporting

confidence: 91%

Protective Role of Ginger against Metformin Induced Alteration in Bcl2 Expression in the Spleen of Normoglycemic Albino Rat

Hashish¹

2019

J Histol Histopathol

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“…The balance between Treg and Teff cells has been the focus of the pathological examination of numerous autoimmune disorders, such as uveitis, scleroderma and rheumatoid arthritis (9,10,22). Treg cells, which are a subset of T cells, serve a vital role in peripheral immune tolerance maintenance (23), and Teff cells have the function of regulating immunity and inflammation (9).…”

Section: Discussionmentioning

confidence: 99%

“…Melanocytes may be targeted or destroyed by T-cellmediated immune responses initiated by autoimmune diseases (8). Effector T cells (Teff cells), mainly T helper 1 (Th1) and Th17 cells, are pro-inflammatory T cells that may induce the development and progression of autoimmune processes, while regulatory T cells (Treg cells) serve protective and anti-inflammatory roles (9) and are downregulated in autoimmune diseases (10). In multiple diseases, including skin diseases, an imbalance between Treg and Teff cells is detected, as Treg cells are decreased and Teff cells are increased (11).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‑21‑5p protects melanocytes via targeting STAT3 and modulating Treg/Teff balance to alleviate vitiligo

Huo

Liu

et al. 2020

Mol Med Rep

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Vitiligo (VIT) is caused by loss and degradation of functional epidermal melanocytes. Studies have indicated that melanocyte destruction may be associated with an imbalance between regulatory T cells (Treg cells) and effector T cells (Teff cells). The current study aimed to investigate the molecular mechanism through which Treg/Teff balance affects VIT pathogenesis. To explore this, peripheral blood mononuclear cells were isolated from patients with VIT and healthy individuals. The present study revealed that the proportions of CD4 + T cells, Treg cells and T helper 1 (Th1) cells were decreased in patients with VIT, but those of Teff cells (Th17 and Th22 cells) were increased; additionally, Foxp3 expression was decreased, but the expression levels of interferon-γ, interleukin (IL)-17A and IL-22 were increased. Furthermore, in patients with VIT, microRNA (miR)-21-5p expression was decreased, while that of STAT3 was increased. Further in vitro experiments in CD4 + T cells revealed that STAT3 was targeted by miR-21-5p. Functional analysis further indicated that miR-21-5p overexpression in Th17-polarized CD4 + T cells decreased the proportion of Teff cells and associated cytokines, such as IL-17A and IL-22, but increased the proportion of Treg cells and Foxp3. However, the effects of miR-21-5p overexpression were partly reversed by STAT3 overexpression. Increased apoptosis of melanocytes was detected after co-culture with Th17-polarized CD4 + T cells in the presence of a miR-21-5p mimic. However, this indirect effect of the miR-21-5p mimic on melanocytes was decreased via STAT3 overexpression. Therefore, miR-21-5p may protect melanocytes via targeting STAT3 and regulating Treg/Teff balance. The current findings may provide a possible treatment method for managing VIT.

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“…To identify the therapeutic effects of metformin on scleroderma, we used a bleomycin (BLM)-induced murine model of scleroderma. Metformin ameliorates scleroderma in similar mouse models; however, the detailed mechanisms remain unclear [30,31]. In this study, we demonstrated that metformin ameliorates scleroderma in a mouse model by inhibiting Th17 cells via the regulation of mTOR-STAT3 signaling.…”

Section: Introductionmentioning

confidence: 71%

“…These results demonstrate that metformin has both immunoregulatory effects and inhibitory functions in skin. Two other groups have shown that metformin ameliorates scleroderma in BLM-induced mice [30,31]. However, those studies focused on histological pathology, regulatory T cells, and effector T cells.…”

Section: Discussionmentioning

confidence: 99%

Metformin Ameliorates Scleroderma Via Inhibiting Th17 Cells and Reducing mTOR-STAT3 Signaling in Skin Fibroblasts

Moon

Lee

Choi

et al. 2021

Preprint

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Scleroderma is an autoimmune disease that causes dermal fibrosis. It occurs when collagen accumulates in tissue as a result of persistent inflammation. Th17 cells and pro-inflammatory cytokines such as IL-1β, IL-6, IL-17, and TNF-α play important roles in the pathogenesis of scleroderma. Because metformin, a medication used to treat diabetes, has effective immunoregulatory functions, we investigated its therapeutic function in scleroderma. Mice in a model of bleomycin-induced scleroderma were treated with metformin for 2 weeks. Histological assessment demonstrated protective effects of metformin against scleroderma. Metformin decreased the expression of pro-inflammatory factors in dermal tissue and lymphocytes. It also decreased mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6, IL-17, and TNF-α) and fibrosis-inducing molecules both in vivo and in vitro. These results suggest that metformin treatment has anti-inflammatory effects on lymphocytes via the inhibition of IL-17 and cytokines related to Th17 differentiation, such as IL-1β, IL-6, and TNF-α. To investigate how metformin modulates the inflammatory process in skin fibroblasts, we measured mTOR-STAT3 signaling in skin fibroblasts and found that mTOR and STAT3 protein expression were decreased by metformin treatment. These results suggest that metformin has potential to treat scleroderma by inhibiting pro-inflammatory cytokines and anti-inflammatory activity mediated by mTOR-STAT3 signaling.

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Metformin attenuates bleomycin-induced scleroderma by regulating the balance of Treg/Teff cells and reducing spleen germinal center formation

Cited by 23 publications

References 29 publications

Protective Role of Ginger against Metformin Induced Alteration in Bcl2 Expression in the Spleen of Normoglycemic Albino Rat

Protective Role of Ginger against Metformin Induced Alteration in Bcl2 Expression in the Spleen of Normoglycemic Albino Rat

MicroRNA‑21‑5p protects melanocytes via targeting STAT3 and modulating Treg/Teff balance to alleviate vitiligo

Metformin Ameliorates Scleroderma Via Inhibiting Th17 Cells and Reducing mTOR-STAT3 Signaling in Skin Fibroblasts

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