2. Academic Validation
  3. Aristolochic acid IVa ameliorates arthritis in SKG Mice by regulating macrophage polarization and Th17/Treg balance

Aristolochic acid IVa ameliorates arthritis in SKG Mice by regulating macrophage polarization and Th17/Treg balance

  • Phytomedicine. 2025 Apr:139:156557. doi: 10.1016/j.phymed.2025.156557.
Qin-Wen Gao 1,  Wei-Ying Liu 2,  Mirza Jawad 3,  Lei Ci 4,  Yi-Yi Cao 1,  Jing Xi 1,  Jia-Ying Wu 1,  Yu-Yang Lei 1,  Yu-Shi Hu 1,  Xin-Yue You 1,  Xin-Yu Zhang 1,  Jian Fei 5,  Yang Luan 6
Affiliations

Affiliations

  • 1 School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 2 School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
  • 3 The Center for Bioinformatics and Computational Biology, Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
  • 4 Shanghai Engineering Research Center for Model Organisms, SMOC, Shanghai 201203, China.
  • 5 Shanghai Engineering Research Center for Model Organisms, SMOC, Shanghai 201203, China; School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. Electronic address: jfei@tongji.edu.cn.
  • 6 School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: yluan@sjtu.edu.cn.
PMID: 40043543 DOI: 10.1016/j.phymed.2025.156557
Abstract

Background: Aristolochic acids (AAs)-containing herbs have been used as medicinal remedies for thousands of years. However, exposure to AAI and AAII increases the risk of nephropathy and cancers. Our previous study identified AAIVa, an analogue without carcinogenicity or nephrotoxicity, exerted anti-inflammatory effects.

Purpose: To explore AAIVa's anti-inflammatory mechanisms and assess its therapeutic potential in arthritis.

Methods and results: In this study, we employed in vitro assays on RAW 264.7 cells and explored the underlying mechanisms of AAIVa's anti-inflammatory effect through transcriptome analysis, identifying macrophage polarization-associated genes, IL-17 signaling, and Rheumatoid Arthritis (RA) pathway. Also, we used BALB/cAnSmoc-Zap70em(W163C)Smoc (SKG) mice, a model that spontaneously develops chronic arthritis closely resembling human RA, and revealed AAIVa's therapeutic potential in arthritis. AAIVa-treatment (10 mg/kg, i.g.) for 4 weeks protected SKG mice from mannan-accelerated arthritis symptoms, reducing inflammation and improving bone microstructure. We further isolated bone marrow-derived macrophages (BMDMs) and spleen primary cells from SKG and BALB/c mice to evaluate the impact of AAIVa on macrophage polarization and T cell differentiation. We found that AAIVa induced M2 macrophage polarization in BMDMs, and mitigated lipopolysaccharide-stimulated inflammation by increasing Tregs and decreasing Th17 cells. Subsequently, the elevation of M2 macrophages, increased Tregs expression and decreased Th17 cells in the ankle joints of SKG mice supported our in vitro observation.

Conclusion: We provide first evidence that AAIVa exerts anti-arthritis effects, likely through modulation of macrophage polarization and restoration of the Th17/Treg balance. Our findings highlight AAIVa's mechanism of action and AAIVa's potential as a therapeutic candidate for autoimmune arthritis.

Keywords

Anti-inflammatory effect; Aristolochic acid IVa; Macrophage polarization; Rheumatoid arthritis; Th17/Treg balance.

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