Interleukin-35 -producing B cells rescues inflammatory bowel disease in a mouse model via STAT3 phosphorylation and intestinal microbiota modification

Minxiang Xie; Yuzhen Zhu; Yunjiao Zhou; Qiao Wang; Erli Gu; Yiwei Chu; Luman Wang

doi:10.1038/s41420-023-01366-5

Interleukin-35 -producing B cells rescues inflammatory bowel disease in a mouse model via STAT3 phosphorylation and intestinal microbiota modification

Cell Death Discov. 2023 Feb 17;9(1):67. doi: 10.1038/s41420-023-01366-5.

Authors

Minxiang Xie^{1

2}, Yuzhen Zhu³, Yunjiao Zhou², Qiao Wang², Erli Gu³, Yiwei Chu^#^{4

5}, Luman Wang^#^{6

7}

Affiliations

¹ Department of Immunology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
² Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
³ Department of gastroenterology, Jing'an District Central Hospitals, Fudan University, Shanghai, China.
⁴ Department of Immunology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. yiweichu@fudan.edu.cn.
⁵ Biotherapy Research Center, Fudan University, Shanghai, 200032, China. yiweichu@fudan.edu.cn.
⁶ Department of Immunology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. lumanwang@fudan.edu.cn.
⁷ Department of Endocrinology and Metabolism, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China. lumanwang@fudan.edu.cn.

^# Contributed equally.

Abstract

Interleukin-35 (IL-35)-producing B cells (IL-35⁺B cells) play an important role in diseases, and the expansion of IL-35⁺ immune cells have been observed in inflammatory bowel disease (IBD). However, how IL-35⁺B cells function and the manner in which they perform their roles remain unclear. In this study, human samples and animal models were used to confirm the expansion of IL-35⁺B cells during IBD. In addition, by using il12a^-/- and ebi3^-/- mice, we demonstrated that the regulatory role of B cells in IBD depends on IL-35. Mechanically, IL-35⁺B cells can promote its own expansion through endocrine actions and depend on the transcription factor signal transducer and activator of transcription 3. Interestingly, we found that the diversity of intestinal microbes and expression of microbial metabolites decreased during IBD. IL-35⁺B cells promote the high expression of indoleacetic acid (IAA), and exogenous metabolite supplementation with IAA can further promote the expansion of IL-35⁺B cells and rescues the disease. This study provides a new concept for the regulatory model of B cells and a new approach for the treatment of IBD.