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Metformin Ameliorates Scleroderma Via Inhibiting Th17 Cells and Reducing mTOR-STAT3 Signaling in Skin Fibroblasts
Mi-La Cho
Catholic University of Korea
Corresponding Author
ORCiD: https://orcid.org/0000-0001-5715-3989
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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.
Keywords
Metformin, Scleroderma, Inflammation, STAT3, mTOR
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CURRENT STATUS: Under Review
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Posted 07 Jan, 2021
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Review #2 received
Received 08 Jan, 2021
Reviewer #3 agreed
On 05 Jan, 2021
Reviewer #4 agreed
On 05 Jan, 2021
Reviewer #2 agreed
On 05 Jan, 2021
Reviewers invited
Invitations sent on 04 Jan, 2021
Reviewer #1 agreed
On 04 Jan, 2021
Editor assigned
On 29 Dec, 2020
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On 29 Dec, 2020
Editor invited
On 29 Dec, 2020
First submitted
On 27 Dec, 2020
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This preprint is under consideration at Journal of Translational Medicine. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Metformin Ameliorates Scleroderma Via Inhibiting Th17 Cells and Reducing mTOR-STAT3 Signaling in Skin Fibroblasts
Mi-La Cho
Catholic University of Korea
Corresponding Author
ORCiD: https://orcid.org/0000-0001-5715-3989
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 07 Jan, 2021
No community comments so far
Review #2 received
Received 08 Jan, 2021
Reviewer #3 agreed
On 05 Jan, 2021
Reviewer #4 agreed
On 05 Jan, 2021
Reviewer #2 agreed
On 05 Jan, 2021
Reviewers invited
Invitations sent on 04 Jan, 2021
Reviewer #1 agreed
On 04 Jan, 2021
Editor assigned
On 29 Dec, 2020
Submission checks complete
On 29 Dec, 2020
Editor invited
On 29 Dec, 2020
First submitted
On 27 Dec, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Translational Medicine
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5