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PDE4 inhibitor apremilast ameliorates TNBS-induced irritable bowel syndrome in mice by activating the Nrf-2 signaling pathway in enteric glial cells

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Enteric glial cells (EGCs) play an important role in the pathogenesis of irritable bowel syndrome (IBS). Phosphodiesterase-4 (PDE4) functions as a catalyzing enzyme targeting hydrolyzation of intracellular cyclic adenosine monophosphate (cAMP). Increased PDE4 activity promotes excessive production of pro-inflammatory cytokines and chemokines in various immune and epithelial cells, exacerbating immune cell activation and infiltration in inflamed tissues, inhibition of PDE4 has been proven to be an important strategy for inflammatory and autoimmune diseases. In this study we investigated the pathological role of PDE4 and the therapeutic effects of a PDE4 inhibitor apremilast in IBS. 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced IBS model was established in mice, the mice were treated with apremilast (50 mg/kg, i.g.) for 7 days. After treatment, the intestinal motility and visceral sensitivity were assessed. At the end of the study, the mice were euthanized and the blood and colon tissues were collected for analyses. We showed that apremilast treatment significantly ameliorated IBS symptoms in the mice, evidenced by improvement on delayed intestinal motility and visceral hypersensitivity. We found that EGCs were activated in the colon of IBS mice. We then demonstrated that apremilast (10 μM) significantly suppressed TNF-α/IFN-γ stimulated activation of rat EGC cell line CRL-2690 and primary EGCs in vitro, as well as the secretion of EGCs-derived pain mediators and inflammatory factors while ameliorating oxidative stress. These effects depended on the activation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling pathway, which was validated in Nrf-2 knockout EGCs. These results suggest that inhibition of PDE4 by apremilast suppresses EGCs activation by activating the Nrf-2 signaling pathway, leading to decreased expression of pain mediators and inflammatory factors while ameliorating oxidative stress, ultimately alleviating IBS.

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Fig. 1: Apremilast attenuated the experimental manifestations of IBS by suppressing EGCs activation.
Fig. 2: Apremilast downregulated the secretion of pain mediators and inflammatory factors as well as ameliorated intestinal oxidative stress in IBS.
Fig. 3: Apremilast suppressed the activation of TNF-α/IFN-γ treated EGCs.
Fig. 4: Apremilast reduced the expression of pain mediators and inflammatory factors in TNF-α/IFN-γ stimulated EGCs.
Fig. 5: Apremilast ameliorated oxidative stress in EGCs by activating the Nrf-2 signaling pathway.
Fig. 6: Apremilast regulated the activation and function of EGCs in an Nrf-2 dependent manner.
Fig. 7: Apremilast ameliorated oxidative stress in EGCs in an Nrf-2 dependent manner.
Fig. 8: Apremilast regulates the activation and function of EGCs to ameliorate irritable bowel syndrome via the Nrf-2 pathway.

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Acknowledgements

This work was granted by National Natural Science Foundation of China (82173822) and Strategic Priority Research Program of the Chinese Academy of Sciences (XDB1060000). We thank that Prof Hai-yan Zhang for her kind assistance to this study.

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  1. These authors contributed equally: Yu-hao Lu, Shu-yue Lei

Authors and Affiliations

  1. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Yu-hao Lu, Shu-yue Lei, Tao Yang, You-sheng Xu, Hong-lin Wang, Chun-lan Feng & Wei Tang

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Yu-hao Lu, Shu-yue Lei, Tao Yang, You-sheng Xu, Hong-lin Wang & Wei Tang

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  1. Yu-hao Lu
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Contributions

YHL, SYL, TY, and WT designed project and contributed to the conception. YHL, SYL, YSX, HLW, and CLF performed research. YHL, SYL, and TY analyzed data. YHL, SYL, and WT wrote the paper. All authors contributed to the collection and interpretation of data and approved the final draft.

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Correspondence to Wei Tang.

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Lu, Yh., Lei, Sy., Yang, T. et al. PDE4 inhibitor apremilast ameliorates TNBS-induced irritable bowel syndrome in mice by activating the Nrf-2 signaling pathway in enteric glial cells. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01649-w

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