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Resatorvid (TAK-242) Ameliorates Ulcerative Colitis by Modulating Macrophage Polarization and T Helper Cell Balance via TLR4/JAK2/STAT3 Signaling Pathway

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Abstract

Resatorvid (TAK-242), a specific inhibitor of Toll-like receptor-4 (TLR4), has attracted attention for its anti-inflammatory properties. Despite this, few studies have evaluated its effects on ulcerative colitis (UC). This study aimed to investigate the effects of TAK-242 on macrophage polarization and T helper cell balance and the mechanism by which it alleviates UC. Our findings indicated that TLR4 expression was elevated in patients with UC, a mouse model of UC, and HT29 cells undergoing an inflammatory response. TAK‑242 treatment reduced apoptosis in TNF-α and LPS-stimulated HT29 cells and alleviated symptoms of dextran sulfate sodium (DSS)‑induced colitis in vivo. TAK‑242 downregulated TLR4 expression and decreased the secretion of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β while enhancing IL-10 production. TAK-242 also reduced M1 macrophage polarization and diminished Th1 and Th17 cell infiltration while increasing Th2 cell infiltration and M2 macrophage polarization both in vitro and in vivo. Mechanistically, TAK-242 inhibited the JAK2/STAT3 signaling pathway, an important regulator of macrophage polarization and T helper cell balance. Furthermore, the in vivo and in vitro effects of TAK-242 were partially negated by the administration of the JAK2/STAT3 antagonist AG490, suggesting that TAK-242 inhibits the JAK2/STAT3 pathway to exert its biological activities. Taken together, this study underscores TAK-242 as a promising anti-UC agent, functioning by modulating macrophage polarization and T helper cell balance via the TLR4/JAK2/STAT3 signaling pathway.

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Funding

This work was supported by the Natural Science Foundation of Xinjiang Uygur Autonomous Region (No: 2022D01C632).

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Authors and Affiliations

  1. Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830001, Xinjiang Uygur Autonomous Region, China

    Xiaoling Huang, Huan Liu, Mengying Dai, Jiejie Guo, Wenjia Hui, Weidong Liu, Milamuguli Haerken, Ruixue Zheng, Tangnuer Yushanjiang & Feng Gao

  2. Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China

    Rong Lin

  3. Department of Gastroenterology, Xinjiang Clinical Research Center for Digestive Diseases, 830001, Urumqi, Xinjiang Uygur Autonomous Region, China

    Xiaoling Huang, Huan Liu, Mengying Dai, Jiejie Guo, Wenjia Hui, Weidong Liu, Milamuguli Haerken, Ruixue Zheng, Tangnuer Yushanjiang & Feng Gao

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  1. Xiaoling Huang
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Contributions

XH, RL, and FG conceived and designed the experiments. XH, RL, HL, MD, JG, WH, WL and MH contributed significantly to the experiments and arranging data. RZ and TY performed data analyses. XH wrote the draft manuscript. FG revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Feng Gao.

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All patients provided their written, voluntarily informed consent. All human and animal-related procedures were carried out in accordance with the guidelines outlined in the Helsinki Declaration, and this study was approved by the Ethics Committee of the Xinjiang Yugur Autonomous Region People’s Hospital.

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Huang, X., Lin, R., Liu, H. et al. Resatorvid (TAK-242) Ameliorates Ulcerative Colitis by Modulating Macrophage Polarization and T Helper Cell Balance via TLR4/JAK2/STAT3 Signaling Pathway. Inflammation (2024). https://doi.org/10.1007/s10753-024-02028-z

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