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Thalidomide Attenuates Colitis and Is Associated with the Suppression of M1 Macrophage Polarization by Targeting the Transcription Factor IRF5

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Abstract

Background

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. The TNF-α inhibitor thalidomide is reported to be effective for inducing remission in pediatric Crohn’s disease (CD) and adults with refractory CD. The mechanisms underlying the immunomodulatory and anti-inflammatory properties of thalidomide are unclear.

Methods

Histological assessments were firstly performed in thalidomide treated UC patients. Then the effect of thalidomide in vivo was detected in DSS-induced murine colitis. The mechanism involving IRF5, and M1 macrophage polarization was investigated by using plasmid transfection, western blotting, and real-time PCR. Finally, AOM/DSS model was used to detect the role of thalidomide in colitis associated cancer.

Results

We first found that treatment with thalidomide could ameliorate colon inflammation for 8 weeks and promote mucosal healing in human UC. Moreover, treatment with thalidomide protected mice from dextran sodium sulfate (DSS)-induced acute colitis, with treated mice presenting with a higher body weight, lower histological score, and lower DAI. Concomitantly, in comparison with control mice, mice treated with thalidomide showed accelerated recovery following colitis after 10 days of thalidomide treatment. Mechanistically, we observed that thalidomide could increase epithelial cell self-renewal capacity and modulate M1/M2 polarization by decreasing M1 markers CD86 and CCR7 and increasing M2 protein signatures CD206 and Arg-1. Thalidomide controls M1 macrophage polarization by targeting the transcription factor IRF5. Finally, by using the classical AOM/DSS model, we found that thalidomide-treated mice presented with a lower incidence and growth of colitis-associated carcinoma (CAC) than negative control mice.

Conclusions

In summary, thalidomide suppresses M1 polarization in the inflammatory microenvironment, which not only attenuates colonic inflammation to facilitate mucosal healing after DSS-induced injury but also represses the progression of CAC.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

The study was sponsored by the National Natural Science Foundation of China (No. 81900478) and the Natural Science Foundation of Hunan Province (No. 2020JJ5801), China.

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Authors and Affiliations

  1. Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China

    Jiaxi Lu, Deliang Liu, Yuyong Tan, Rong Li, Xuehong Wang & Feihong Deng

  2. Research Center of Digestive Disease, Central South University, Changsha, 410011, Hunan, China

    Jiaxi Lu, Deliang Liu, Yuyong Tan, Rong Li, Xuehong Wang & Feihong Deng

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  1. Jiaxi Lu
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  2. Deliang Liu
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Correspondence to Feihong Deng.

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Lu, J., Liu, D., Tan, Y. et al. Thalidomide Attenuates Colitis and Is Associated with the Suppression of M1 Macrophage Polarization by Targeting the Transcription Factor IRF5. Dig Dis Sci 66, 3803–3812 (2021). https://doi.org/10.1007/s10620-021-07067-2

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