Tolerogenic dendritic cell-mediated regulatory T cell differentiation by Chinese herbal formulation attenuates colitis progression

Chunhua Huang; Cheng Lyu; Heung-Lam Mok; Yiqi Xu; Ka-Wing Cheng; Cheng Zhang; Die Hu; Lin Zhu; Chengyuan Lin; Xin Chen; Hor-Yue Tan; Zhaoxiang Bian

doi:10.1016/j.jare.2024.04.023

Tolerogenic dendritic cell-mediated regulatory T cell differentiation by Chinese herbal formulation attenuates colitis progression

J Adv Res. 2024 Apr 26:S2090-1232(24)00167-X. doi: 10.1016/j.jare.2024.04.023. Online ahead of print.

Authors

Chunhua Huang¹, Cheng Lyu², Heung-Lam Mok², Yiqi Xu², Ka-Wing Cheng¹, Cheng Zhang³, Die Hu¹, Lin Zhu², Chengyuan Lin², Xin Chen⁴, Hor-Yue Tan⁵, Zhaoxiang Bian⁶

Affiliations

¹ Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong Special Administrative Region of China; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong Special Administrative Region of China.
² Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong Special Administrative Region of China.
³ School of Chinese Medicine, The University of Hong Kong, Hong Kong Special Administrative Region of China.
⁴ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau Special Administrative Regions of China.
⁵ Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong Special Administrative Region of China; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong Special Administrative Region of China. Electronic address: hyhtan@hkbu.edu.hk.
⁶ Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong Special Administrative Region of China; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong Special Administrative Region of China. Electronic address: bzxiang@hkbu.edu.hk.

PMID: 38677546
DOI: 10.1016/j.jare.2024.04.023

Abstract

Introduction: Ulcerative colitis (UC) is a chronic inflammatory disease characterized by loss of immune tolerance to luminal antigens and progressive intestinal tissue injury. Thus, the re-establishment of immune tolerance is crucial for suppressing aberrant immune responses and UC progression.

Objectives: This study aimed to investigate the mechanisms underlying the action of CDD-2103 and its bioactive compounds in mediating immune regulation in mouse models of colitis.

Methods: Two experimental colitis models, chronic 2,4,6-trinitrobenzene sulfonic acid (TNBS)- and T-cell transfer-induced Rag1^-/- mice, were used to determine the effects of CDD-2103 on colitis progression. Single-cell transcriptome analysis was used to profile the immune landscape and its interactions after CDD-2103 treatment. Liquid chromatography-mass spectrometry (LC-MS) was used to analyze the major components interacting with lymphoid cells. A primary cell co-culture system was used to confirm the effects of bioactive component.

Results: CDD-2103 dose-dependently suppresses the progression of colitis induced by chemicals or T cell transplantation in Rag1^-/- mice. The effect of CDD-2103 is primarily attributable to an increase in the de novo generation of regulatory T cells (Tregs) in the lamina propria (LP). Single-cell transcriptomic analysis revealed that CDD-2103 treatment increased the number of tolerogenic dendritic cells (DCs). Mechanistically, CDD-2103 promoted tolerogenic DCs accumulation and function by upregulating several genes in the electron transport chain related to oxidative phosphorylation, leading to increased differentiation of Tregs. Further LC-MS analysis identified several compounds in CDD-2103, particularly those distributed within the mesenteric lymph nodes of mice. Subsequent studies revealed that palmatine and berberine promoted tolerogenic bone marrow-derived dendritic cells (BMDC)-mediated Treg differentiation.

Conclusion: Overall, our study demonstrated that the clinically beneficial effect of CDD-2103 in the treatment of UC is based on the induction of immune tolerance. In addition, this study supports berberine and palmatine as potential chemical entities in CDD-2103 that modulate immune tolerance.

Keywords: CDD-2103; Chinese herbal formulation; Oxidative phosphorylation; Regulatory T cell; Tolerogenic dendritic cell; Ulcerative colitis.