2. Academic Validation
  3. Kurarinone regulates Th17/Treg balance and ameliorates autoimmune uveitis via Rac1 inhibition

Kurarinone regulates Th17/Treg balance and ameliorates autoimmune uveitis via Rac1 inhibition

  • J Adv Res. 2024 Mar 24:S2090-1232(24)00113-9. doi: 10.1016/j.jare.2024.03.013.
Chenyang Gu 1,  Yidan Liu 1,  Jianjie Lv 1,  Chun Zhang 2,  Zhaohao Huang 1,  Qi Jiang 1,  Yuehan Gao 1,  Tianyu Tao 1,  Yuhan Su 3,  Binyao Chen 1,  Renbing Jia 4,  Xiuxing Liu 5,  Wenru Su 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China.
  • 2 Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 3 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China; Department of Clinical Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510060, China.
  • 4 Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China.
  • 5 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China. Electronic address: [email protected].
  • 6 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China. Electronic address: [email protected].
PMID: 38522752 DOI: 10.1016/j.jare.2024.03.013
Abstract

Introduction: Autoimmune uveitis (AU) is a severe intraocular autoimmune disorder with a chronic disease course and a high rate of blindness. Kurarinone (KU), a major component of the traditional Chinese medicine Sophorae Flavescentis Radix, possesses a wide spectrum of activities and has been used to treat several inflammation-related diseases.

Objective: We aimed to investigate the effects of KU on AU and its modulatory mechanisms.

Methods: We used an experimental autoimmune uveitis (EAU) animal model and characterized the comprehensive immune landscape of KU-treated EAU mice using single-cell RNA sequencing (scRNA-seq). The retina and lymph nodes were analyzed. The siRNAs and selective inhibitors were used to study the signaling pathway. The effect of KU on peripheral blood mononuclear cells (PBMCs) from uveitis patients was also examined.

Results: We found that KU relieved chorioretinal lesions and immune cell infiltration in EAU model mice. Subsequent single-cell analysis revealed that KU downregulated the EAU-upregulated expression of inflammatory and autoimmune-related genes and suppressed pathways associated with immune cell differentiation, activation, and migration in a cell-specific manner. KU was implicated in restoring T helper 17 (Th17)/regulatory T (Treg) cell balance by alleviating inflammatory injury and elevating the expression of modulatory mediators in Tregs, while simultaneously ameliorating excessive inflammation by Th17 cells. Furthermore, Rac1 and the Id2/Pim1 axis potentiated the pathogenicity of Th17 cells during EAU, which was inhibited by KU treatment, contributing to the amelioration of EAU-induced inflammation and treatment of AU. In addition, KU suppressed inflammatory cytokine production in activated human PBMCs by inhibiting Rac1. Integration of the glucocorticoid-treated transcriptome suggests that KU has immunomodulatory effects on lymphocytes.

Conclusion: Our study constructed a high-resolution atlas of the immunoregulatory effects of KU treatment on EAU and identified its potential therapeutic mechanisms, which hold great promise in treating autoimmune disorders.

Keywords

Autoimmune uveitis; Kurarinone; Rac1; Single-cell RNA sequencing; Th17; Treg.

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