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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

IL-10 Beyond Immunosuppression: Unraveling Spatial, Cellular, and Metabolic Mechanisms of Gut Protection

  • Yuchen Zhang1
  • Xiaohui Liu2
  • Boya Wang3
  • Haoyuan Yin1
  • Xiang Tian1
  • Jiatong Zhao1
  • Shuzi Xin2
  • Hongli Wang2
  • Yushuo Ren1
  • Xinyue Liu1
  • Jingyu Liu1
  • Yuhang Bian1
7 more authors
  • Sijin Gu1
  • Haoxuan Zhang1
  • Tong Wei1
  • Lei Gao4
  • Xin Lu5
  • Hongwei Shang5
  • Jingdong Xu2
5 affiliations
  1. 1Department of Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
  2. 2Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
  3. 3Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
  4. 4Department of Intelligent Medical Engineering, School of Biomedical Engineering, Capital Medical University, Beijing 100069, China
  5. 5Experimental Centre for Morphological Research Platform, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
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Abstract

Intestinal homeostasis requires immune tolerance, barrier integrity, tissue repair, and microbiota mutualism. Interleukin-10 (IL-10) is essential, but not merely as an immunosuppressant. Although IL-10 signals via the IL-10R—JAK1/TYK2—STAT3 axis, its outputs are cell-type and context dependent. In macrophages, IL-10 restrains IL-23 production, inflammasome activation, IL-1β release, and metabolic reprogramming. In T cells, it limits pathogenic T helper 17 cell (Th17) responses while stabilizing regulatory cells and promoting metabolically driven IL-10 production. In the epithelium, IL-10 maintains barrier integrity by limiting apoptosis, endoplasmic reticulum (ER) stress, and mucus defects. IL-10 and the gut microbiota engage in reciprocal regulation: microbial metabolites and structural components enhance IL-10 production and receptor responsiveness, whereas IL-10 signaling preserves microbial diversity and ecological resilience. This may help to explain why systemic recombinant IL-10 failed in Crohn’s disease (CD)—increasing ligand abundance alone is unlikely to recapitulate endogenous localization or restore refractory target cells. Emerging strategies aim to tune IL-10 signaling through gut-selective delivery, engineered cytokines, conditionally activated prodrugs, regulatory cell approaches, and microbiome or metabolic interventions. Clinical translation requires biomarkers of IL-10R expression, STAT3 responsiveness, macrophage metabolic state, microbial signatures, and acquired IL-10 hyporesponsiveness. Despite the established role of IL-10 in intestinal homeostasis, systemic IL-10 therapy has failed in clinical trials, and there is a lack of effective strategies to restore IL-10 signaling in a spatially and cell-specific manner. The spatially organized, metabolically conditioned homeostatic IL-10 signaling—largely inferred from model systems and awaiting direct spatial validation in human intestine—offers a roadmap for more precise therapy in inflammatory bowel disease and related intestinal disorders.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026il10,
  title = {{IL-10 Beyond Immunosuppression: Unraveling Spatial, Cellular, and Metabolic Mechanisms of Gut Protection}},
  author = {Yuchen Zhang and Xiaohui Liu and Boya Wang and Haoyuan Yin and Xiang Tian and Jiatong Zhao and Shuzi Xin and Hongli Wang and Yushuo Ren and Xinyue Liu and Jingyu Liu and Yuhang Bian and Sijin Gu and Haoxuan Zhang and Tong Wei and Lei Gao and Xin Lu and Hongwei Shang and Jingdong Xu},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27219472},
  url = {https://www.mdpi.com/1422-0067/27/21/9472},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - IL-10 Beyond Immunosuppression: Unraveling Spatial, Cellular, and Metabolic Mechanisms of Gut Protection
AU  - Yuchen Zhang
AU  - Xiaohui Liu
AU  - Boya Wang
AU  - Haoyuan Yin
AU  - Xiang Tian
AU  - Jiatong Zhao
AU  - Shuzi Xin
AU  - Hongli Wang
AU  - Yushuo Ren
AU  - Xinyue Liu
AU  - Jingyu Liu
AU  - Yuhang Bian
AU  - Sijin Gu
AU  - Haoxuan Zhang
AU  - Tong Wei
AU  - Lei Gao
AU  - Xin Lu
AU  - Hongwei Shang
AU  - Jingdong Xu
PY  - 2026
DA  - 2026/10/23
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219472
UR  - https://www.mdpi.com/1422-0067/27/21/9472
AB  - Intestinal homeostasis requires immune tolerance, barrier integrity, tissue repair, and microbiota mutualism. Interleukin-10 (IL-10) is essential, but not merely as an immunosuppressant. Although IL-10 signals via the IL-10R—JAK1/TYK2—STAT3 axis, its outputs are cell-type and context dependent. In macrophages, IL-10 restrains IL-23 production, inflammasome activation, IL-1β release, and metabolic reprogramming. In T cells, it limits pathogenic T helper 17 cell (Th17) responses while stabilizing regulatory cells and promoting metabolically driven IL-10 production. In the epithelium, IL-10 maintains barrier integrity by limiting apoptosis, endoplasmic reticulum (ER) stress, and mucus defects. IL-10 and the gut microbiota engage in reciprocal regulation: microbial metabolites and structural components enhance IL-10 production and receptor responsiveness, whereas IL-10 signaling preserves microbial diversity and ecological resilience. This may help to explain why systemic recombinant IL-10 failed in Crohn’s disease (CD)—increasing ligand abundance alone is unlikely to recapitulate endogenous localization or restore refractory target cells. Emerging strategies aim to tune IL-10 signaling through gut-selective delivery, engineered cytokines, conditionally activated prodrugs, regulatory cell approaches, and microbiome or metabolic interventions. Clinical translation requires biomarkers of IL-10R expression, STAT3 responsiveness, macrophage metabolic state, microbial signatures, and acquired IL-10 hyporesponsiveness. Despite the established role of IL-10 in intestinal homeostasis, systemic IL-10 therapy has failed in clinical trials, and there is a lack of effective strategies to restore IL-10 signaling in a spatially and cell-specific manner. The spatially organized, metabolically conditioned homeostatic IL-10 signaling—largely inferred from model systems and awaiting direct spatial validation in human intestine—offers a roadmap for more precise therapy in inflammatory bowel disease and related intestinal disorders.
SN  - 1422-0067
ER  -