Metformin attenuates graft-versus-host disease via restricting mammalian target of rapamycin/signal transducer and activator of transcription 3 and promoting adenosine monophosphate–activated protein kinase-autophagy for the balance between T helper 17 and Tregs

Park, Min-Jung; Lee, Seon‐Yeong; Moon, Su‐Jin; Son, Hye-Jin; Lee, Sung-Hee; Kim, Min Jung; Byun, Jae-Kyeong; Shin, Dong Yun; Park, Sung-Hwan; Yang, Chul-Woo; Cho, Mi‐La

doi:10.1016/j.trsl.2016.03.006

Cited by 73 publications

(59 citation statements)

References 48 publications

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“…44, 45, 46 In this study, madecassic acid was shown to accelerate AMPK activation, and compound C abolished madecassic acid - induced activation of AMPK and downregulation of ACC1 expression under Th17 - polarizing conditions, indicating that madecassic acid downregulated the ACC1 expression by activating AMPK in Th17 cells. Moreover, both compound C and AMPK siRNA reversed the shift induced by madecassic acid.…”

Section: Discussionmentioning

confidence: 49%

Madecassic acid, the contributor to the anti-colitis effect of madecassoside, enhances the shift of Th17 toward Treg cells via the PPARγ/AMPK/ACC1 pathway

Wang

Wei

et al. 2017

Cell Death Dis

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The imbalance between Th17 and Treg cells substantially contributes to the intestinal immune disturbance and subsequent tissue injury in ulcerative colitis. The triterpenoid-rich fraction of Centella asiatica was able to ameliorate dextran sulfate sodium-induced colitis in mice. Here we explored its active ingredient and underlying mechanism with a focus on restoring the Th17/Treg balance. The four main triterpenoids occurring in C. asiatica were shown to attenuate colitis in mice by oral administration. The most effective ingredient madecassoside lost anti-colitis effect when applied topically in the colon, and madecassic acid was recognized to be the active form of madecassoside. Oral administration of madecassic acid decreased the percentage of Th17 cells and downregulated the expression of RORγt, IL-17A, IL-17F, IL-21 and IL-22 and increased the percentage of Treg cells and the expression of Foxp3 and IL-10 in the colons of mice with colitis, but it did not affect Th1 and Th2 cells. Under Th17-polarizing conditions, madecassic acid downregulated ACC1 expression and enhanced the shift of Th17 cells toward Treg cells, but it did not affect the differentiation of Treg cells under Treg-polarizing conditions. Both compound C and AMPK siRNA inhibited the madecassic acid-mediated downregulation of ACC1 expression and shift of Th17 cells to Treg cells under Th17-polarizing conditions. GW9662, T0070907 and PPARγ siRNA blocked the effect of madecassic acid on AMPK activation, ACC1 expression and shift of Th17 cells to Treg cells. Furthermore, madecassic acid was identified as a PPARγ agonist, as it promoted PPARγ transactivation. The correlation between activation of PPARγ and AMPK, downregulation of ACC1 expression, restoration of Th17/Treg balance and attenuation of colitis by madecassic acid was validated in mice with DSS-induced colitis. In conclusion, madecassic acid was the active form of madecassoside in ameliorating colitis by restoring the Th17/Treg balance via regulating the PPARγ/AMPK/ACC1 pathway.

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Section: Discussionmentioning

confidence: 49%

Madecassic acid, the contributor to the anti-colitis effect of madecassoside, enhances the shift of Th17 toward Treg cells via the PPARγ/AMPK/ACC1 pathway

Wang

Wei

et al. 2017

Cell Death Dis

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“…Metformin can have immunosuppressive effects in a number of models: graft-versus-host disease, lupus, and graft rejection (22–24). In these scenarios, T cells are the ‘dominant force’ at the site of activation, and may be experiencing either the systemic hypoglycemic or lactic acidotic effects of metformin.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia

Scharping

Menk

Whetstone

et al. 2017

Cancer Immunology Research

409

362

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Blockade of the coinhibitory checkpoint molecule PD-1 has emerged as an effective treatment for many cancers, resulting in remarkable responses. However, despite successes in the clinic, most patients do not respond to PD-1 blockade. Metabolic dysregulation is a common phenotype in cancer, but both patients and tumors are metabolically heterogeneous. We hypothesized that the deregulated oxidative energetics of tumor cells present a metabolic barrier to antitumor immunity through the generation of a hypoxic microenvironment and that normalization of tumor hypoxia might improve response to immunotherapy. We show that the murine tumor lines B16 and MC38 differed in their ability to consume oxygen and produce hypoxic environments, which correlated with their sensitivity to checkpoint blockade. Metformin, a broadly prescribed type II diabetes treatment, inhibited oxygen consumption in tumor cells in vitro and in vivo, resulting in reduced intratumoral hypoxia. Although metformin monotherapy had little therapeutic benefit in highly aggressive tumors, combination of metformin with PD-1 blockade resulted in improved intratumoral T-cell function and tumor clearance. Our data suggest tumor hypoxia acts as a barrier to immunotherapy, and that remodeling the hypoxic tumor microenvironment has potential to convert patients resistant to immunotherapy into those that receive clinical benefit.

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“…Thus, approaches that globally induce autophagy after transplant must be approached with caution. Promisingly, however, a recent study has reported the beneficial effect of treatment with metformin, an autophagy-promoting drug, on survival in a model of GVHD (48). This effect was associated with inhibition of mTOR, a decrease in Th1/Th17 differentiation, and an increase in Tregs.…”

Section: Discussionmentioning

confidence: 99%

Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease

et al. 2016

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Metformin attenuates graft-versus-host disease via restricting mammalian target of rapamycin/signal transducer and activator of transcription 3 and promoting adenosine monophosphate–activated protein kinase-autophagy for the balance between T helper 17 and Tregs

Cited by 73 publications

References 48 publications

Madecassic acid, the contributor to the anti-colitis effect of madecassoside, enhances the shift of Th17 toward Treg cells via the PPARγ/AMPK/ACC1 pathway

Madecassic acid, the contributor to the anti-colitis effect of madecassoside, enhances the shift of Th17 toward Treg cells via the PPARγ/AMPK/ACC1 pathway

Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia

Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease

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