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Background and objective <p>Myeloid-derived suppressor cells (MDSCs) play a pivotal role in modulating immune responses, particularly in inflammatory bowel disease and the tumor microenvironment. DOT1-like histone H3K79 methyltransferase (DOT1L) influences gene expression and cellular functions in various cell types, but its function in MDSCs remains unclear. Here, we investigated whether DOT1L promotes MDSC activation in a dextran sulfate sodium (DSS)-induced mouse colitis model and explored the potential involvement of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway.</p> Methods <p>3% DSS-induced mouse model of colitis was established and an adeno-associated virus vector was used to overexpress DOT1L. Hematoxylin and eosin staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining were performed to evaluate pathological damage in the colon. Immunofluorescence was used to assess MDSC activation in the colon. In vitro, an MDSC/T-cell coculture system was established, with JAK2/STAT3 inhibitors or RNA interference to manipulate the pathway. Flow cytometry and enzyme-linked immunosorbent assay were conducted to evaluate MDSC immunosuppressive functions. Western blot was used to assess the phosphorylation of JAK2/STAT3 and the expression of DOT1L.</p> Results <p>The overexpression of DOT1L significantly ameliorated DSS-induced colitis symptoms, reduced the disease activity index, and improved intestinal barrier function. Within MDSCs, DOT1L overexpression enhanced phosphorylation of JAK2 and STAT3, suggesting that DOT1L augments the immunosuppressive capacity of MDSCs via JAK2/STAT3 signaling. In coculture experiments, DOT1L-overexpressing MDSCs more effectively suppressed T-cell proliferation, while treatment with the JAK2/STAT3 inhibitor FLLL32 reversed both MDSC activation and the subsequent inhibition of T-cell proliferation.</p> Conclusion <p>Our study demonstrates that DOT1L activates the JAK2/STAT3 signaling pathway to enhance the immunosuppressive function of MDSCs, thereby exerting an anti-inflammatory effect in DSS-induced colitis. These findings highlight DOT1L’s critical role in regulating immune cell function and provide a theoretical basis for its potential as a novel therapeutic target.</p>

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Histone methyltransferase DOT1L promotes myeloid-derived suppressor cell activation to ameliorate colitis by modulating JAK2/STAT3 signaling

  • 期刊论文

  • 发表日期：

    2025年5月13日

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  • Feng Dong,
  • LiJia Shao,
  • Rui Gong,
  • LiHong Shen,
  • LiMin Wang

摘要

Background and objective

Myeloid-derived suppressor cells (MDSCs) play a pivotal role in modulating immune responses, particularly in inflammatory bowel disease and the tumor microenvironment. DOT1-like histone H3K79 methyltransferase (DOT1L) influences gene expression and cellular functions in various cell types, but its function in MDSCs remains unclear. Here, we investigated whether DOT1L promotes MDSC activation in a dextran sulfate sodium (DSS)-induced mouse colitis model and explored the potential involvement of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway.

Methods

3% DSS-induced mouse model of colitis was established and an adeno-associated virus vector was used to overexpress DOT1L. Hematoxylin and eosin staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining were performed to evaluate pathological damage in the colon. Immunofluorescence was used to assess MDSC activation in the colon. In vitro, an MDSC/T-cell coculture system was established, with JAK2/STAT3 inhibitors or RNA interference to manipulate the pathway. Flow cytometry and enzyme-linked immunosorbent assay were conducted to evaluate MDSC immunosuppressive functions. Western blot was used to assess the phosphorylation of JAK2/STAT3 and the expression of DOT1L.

Results

The overexpression of DOT1L significantly ameliorated DSS-induced colitis symptoms, reduced the disease activity index, and improved intestinal barrier function. Within MDSCs, DOT1L overexpression enhanced phosphorylation of JAK2 and STAT3, suggesting that DOT1L augments the immunosuppressive capacity of MDSCs via JAK2/STAT3 signaling. In coculture experiments, DOT1L-overexpressing MDSCs more effectively suppressed T-cell proliferation, while treatment with the JAK2/STAT3 inhibitor FLLL32 reversed both MDSC activation and the subsequent inhibition of T-cell proliferation.

Conclusion

Our study demonstrates that DOT1L activates the JAK2/STAT3 signaling pathway to enhance the immunosuppressive function of MDSCs, thereby exerting an anti-inflammatory effect in DSS-induced colitis. These findings highlight DOT1L’s critical role in regulating immune cell function and provide a theoretical basis for its potential as a novel therapeutic target.