International immunopharmacology · 2025
5-aminolaevulinic acid combined with sodium ferrous citrate ameliorated collagen-induced arthritis via anti-inflammatory effects and fibroblast-like synoviocytes-driven B cell immunomodulation.
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Ding Zhaolun, Ma Kuai, Kamiya Atsuko, Ito Hidenori, Takahashi Kiwamu, Nakajima Motowo, Wang Chunsheng, Fujino Masayuki, Li Xiao-Kang
Аннотация
PURPOSE: This study evaluated the therapeutic potential of 5-aminolevulinic acid combined with sodium ferrous citrate (5-ALA/SFC) for rheumatoid arthritis (RA), focusing on its dual anti-inflammatory and immunomodulatory properties.
METHODS: Collagen-induced arthritis (CIA) murine models were administered either low (100/157 mg/kg) or high (500/157 mg/kg) doses of 5-ALA/SFC. Disease progression was evaluated using clinical scoring, a histopathological analysis, and micro-computed tomography to assess bone morphology. Synovial inflammation and oxidative stress markers, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, inducible nitric oxide synthase (iNOS), heme oxygenase-1 (HO-1), and indoleamine 2,3-dioxygenase (IDO), were quantified in fibroblast-like synoviocytes (FLSs) using flow cytometry and quantitative reverse transcription polymerase chain reaction. B cell subpopulations, specifically plasmablasts and regulatory B cells (Bregs) in the draining lymph nodes (dLNs), were analyzed by flow cytometry. Human MH7A synovial cells were used to corroborate the FLS-mediated immunoregulatory effects.
RESULTS: 5-ALA/SFC demonstrated significant dose-dependent amelioration of joint swelling, synovial hyperplasia, cartilage, and bone degradation in CIA mice. This treatment significantly attenuated the expression of pro-inflammatory mediators (TNF-α, IL-1β, and iNOS) in FLSs while upregulating the expression of HO-1, IDO, and TNF-stimulated gene-6 (TSG-6). In the dLNs, 5-ALA/SFC reduced the proportion of plasmablasts and increased the percentage of Bregs. In vitro experiments using MH7A cells confirmed that 5-ALA/SFC downregulates B cell-activating factor (BAFF) and vascular cell adhesion molecule-1 (VCAM-1), both of which are critical for B cell maturation, and enhances HO-1 and TSG-6 expression under pro-inflammatory cytokine stimulation.
CONCLUSION: 5-ALA/SFC exerted its therapeutic effects in RA by suppressing synovial inflammation via HO-1/IDO-mediated antioxidant pathways and restoring B cell homeostasis by modulating FLS-derived signals, including BAFF and VCAM-1 in mice. Potential translational limitations include inherent differences between murine CIA models and human RA pathophysiology, as well as the use of immortalized human synovial cell lines instead of primary patient-derived FLSs. These findings underscore the potential of 5-ALA/SFC as a multitarget therapeutic strategy, offering promising prospects for the development of novel RA treatments though clinical translation requires further investigation of long-term safety, optimal dosing, and side effects in humans.
METHODS: Collagen-induced arthritis (CIA) murine models were administered either low (100/157 mg/kg) or high (500/157 mg/kg) doses of 5-ALA/SFC. Disease progression was evaluated using clinical scoring, a histopathological analysis, and micro-computed tomography to assess bone morphology. Synovial inflammation and oxidative stress markers, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, inducible nitric oxide synthase (iNOS), heme oxygenase-1 (HO-1), and indoleamine 2,3-dioxygenase (IDO), were quantified in fibroblast-like synoviocytes (FLSs) using flow cytometry and quantitative reverse transcription polymerase chain reaction. B cell subpopulations, specifically plasmablasts and regulatory B cells (Bregs) in the draining lymph nodes (dLNs), were analyzed by flow cytometry. Human MH7A synovial cells were used to corroborate the FLS-mediated immunoregulatory effects.
RESULTS: 5-ALA/SFC demonstrated significant dose-dependent amelioration of joint swelling, synovial hyperplasia, cartilage, and bone degradation in CIA mice. This treatment significantly attenuated the expression of pro-inflammatory mediators (TNF-α, IL-1β, and iNOS) in FLSs while upregulating the expression of HO-1, IDO, and TNF-stimulated gene-6 (TSG-6). In the dLNs, 5-ALA/SFC reduced the proportion of plasmablasts and increased the percentage of Bregs. In vitro experiments using MH7A cells confirmed that 5-ALA/SFC downregulates B cell-activating factor (BAFF) and vascular cell adhesion molecule-1 (VCAM-1), both of which are critical for B cell maturation, and enhances HO-1 and TSG-6 expression under pro-inflammatory cytokine stimulation.
CONCLUSION: 5-ALA/SFC exerted its therapeutic effects in RA by suppressing synovial inflammation via HO-1/IDO-mediated antioxidant pathways and restoring B cell homeostasis by modulating FLS-derived signals, including BAFF and VCAM-1 in mice. Potential translational limitations include inherent differences between murine CIA models and human RA pathophysiology, as well as the use of immortalized human synovial cell lines instead of primary patient-derived FLSs. These findings underscore the potential of 5-ALA/SFC as a multitarget therapeutic strategy, offering promising prospects for the development of novel RA treatments though clinical translation requires further investigation of long-term safety, optimal dosing, and side effects in humans.