2. Academic Validation
  3. Fraxinellone alleviates colitis-related intestinal fibrosis by blocking the circuit between PD-1+ Th17 cells and fibroblasts

Fraxinellone alleviates colitis-related intestinal fibrosis by blocking the circuit between PD-1+ Th17 cells and fibroblasts

  • Int Immunopharmacol. 2024 May 21:135:112298. doi: 10.1016/j.intimp.2024.112298.
Yuejie Xu 1,  Chang Zheng 2,  Ping Jiang 2,  Siqi Ji 3,  Shafi Ullah 3,  Yu Zhao 4,  Dan Su 5,  Guifang Xu 6,  Mingming Zhang 7,  Xiaoping Zou 8
Affiliations

Affiliations

  • 1 Department of Traditional Chinese and Western Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210046, China.
  • 2 Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing 210093, China.
  • 3 Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China.
  • 4 University of Chicago, Pritzker School of Molecular Engineering, Chicago, IL, 60637, United States.
  • 5 FUJIFILM Diosynth Biotechnologies, Watertown 02472, MA, United States.
  • 6 Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing 210093, China. Electronic address: xuguifang@njglyy.com.
  • 7 Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China. Electronic address: doczmm@sjtu.edu.cn.
  • 8 Department of Traditional Chinese and Western Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210046, China; Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing 210093, China. Electronic address: zouxp@nju.edu.cn.
PMID: 38776854 DOI: 10.1016/j.intimp.2024.112298
Abstract

Background: Excessive activation of colonic fibroblasts and differentiation of T helper 17 (Th17) cells are the key steps for intestinal fibrogenesis in the process of inflammatory bowel disease (IBD). Although both transforming growth factor-beta (TGF-β)/Mothers Against Decapentaplegic Homolog (SMAD) 3-induced fibroblasts activation and interleukin (IL)-6/signal transducer and activator of transcription (STAT) 3-induced Th17 differentiation have been well studied, the crosstalk between fibroblasts and Th17 cells in the process of intestinal fibrogenesis needs to be unveiled.

Methods: In this study, the activation of colonic fibroblasts was induced with dextran sulfate sodium salt (DSS) and TGF-β in vivo and in vitro respectively. P-SMAD3 and its downstream targets were quantified using RT-PCR, western blot and immunofluorescence. The differentiation of programmed death 1 (PD-1) + Th17 and activation of fibroblasts were quantified by FACS. PD-1+ Th17 cells and fibroblasts were co-cultured and cytokines in the supernatant were tested by ELISA. The anti-fibrosis effects of different chemical compounds were validated in vitro and further confirmed in vivo.

Results: The colonic fibroblasts were successfully activated by DSS and TGF-β in vivo and in vitro respectively, as activation markers of fibroblasts (p-SMAD3 and its downstream targets such as Acta2, Col1a1 and CTGF) were significantly increased. The activated fibroblasts produced more IL-6 compared with their inactivated counterparts in vivo and in vitro. The proinflammatory cytokine IL-6 induced PD-1+ Th17 differentiation and TGF-β that in return promoted the activation of colonic fibroblasts. Fraxinellone inhibited TGF-β+ PD-1+ Th17 cells via deactivating STAT3.

Conclusions: The reciprocal stimulation constructed a circuit of PD-1+ Th17 cells and fibroblasts that accelerated the fibrosis process. Fraxinellone was selected as the potential inhibitor of the circuit of PD-1+ Th17 cells and fibroblasts in vivo and in vitro. Inhibiting the circuit of PD-1+ Th17 cells and fibroblasts could be a promising strategy to alleviate intestinal fibrosis.

Keywords

Fibroblasts; Intestinal fibrosis; PD-1; Th17.

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