Moxibustion inhibits the macrophage M1 polarization toll-like receptor 4/myeloid differentiation factor 88/nuclear factor kappa B signaling pathway by regulating T-cell immunoglobulin and mucin-containing protein-3 in rheumatoid arthritis

doi:10.19852/j.cnki.jtcm.2024.06.009

Journal of Traditional Chinese Medicine ›› 2024, Vol. 44 ›› Issue (6): 1227-1235.DOI: 10.19852/j.cnki.jtcm.2024.06.009

• Research Articles • Previous Articles Next Articles

Moxibustion inhibits the macrophage M1 polarization toll-like receptor 4/myeloid differentiation factor 88/nuclear factor kappa B signaling pathway by regulating T-cell immunoglobulin and mucin-containing protein-3 in rheumatoid arthritis

LUO Kun¹, ZHONG Yumei², GUO Yanding¹, ZHANG Linlin¹, HU Danhui¹, MA Wenbin¹, YANG Xin³, ZHOU Haiyan¹()

1 Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
2 Department of Painology, Chengdu Integrated TCM & Western Medicine Hospital/Chengdu First People's Hospital, Chengdu 610095, China
3 Health Rehabilitation School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China

Received:2023-09-11 Accepted:2023-12-05 Online:2024-12-15 Published:2024-11-12
Contact: ZHOU Haiyan
About author:Prof. ZHOU Haiyan, Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China. zhouhaiyan@cdutcm.edu.cn Telephone: +86-13551039390
Supported by:
National Natural Science Foundation of China: Study on Immunoregulatory Mechanism of Moxibustion "Regulating Weiqi" to Regulate the Intrasynovial Environment Steady State in Rheumatoid Arthritis Model Rats based on the Skin-resident Memory T cells- Growth Arrest-specific 6/ Mer Tyrosine Kinase(82374587);National Natural Science Foundation of China: Study on the Immune Mechanisms of Macrophage M1/M2 Polarization in the Treatment of Rheumatoid Arthritis by Moxibustion "Strengthening Body Resistance and Eliminating Evil"(81973959);National Key R&D Program of China: Research on the Functional Characteristics of "Special Effects" and "Common Effects" of Acupoints(2019YFC1709001);Science and Technology Innovation Seedling Project of Sichuan Province: based on Macrophage M1 Polarization Signaling Pathway Toll-like receptor 4/Myeloid differentiation factor 88/Nuclear factor kappa B and its Regulatory Molecule T-cell Immunoglobulin and Mucin-containing Protein-3 Exploring the Effect Mechanism of Moxibustion on Experimental Rheumatoid Arthritis Model(2022037)

Abstract

Abstract:

OBJECTIVE: To explore whether moxibustion exerts therapeutic effects on rheumatoid arthritis (RA) by regulating the expression of T-cell immunoglobulin and mucin-containing protein-3 (TIM-3) and subsequently modulating the macrophage M1 polarization toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-nuclear factor kappa B (NF-κB) signaling pathway.

METHODS: We utilized moxibustion treatment in RA rat models using the Zusanli (ST36) and Shenshu (BL23) acupoints. Hematoxylin and eosin (HE) staining was used to observe the pathological changes of the synovial tissue under a section light microscope, and pathological scoring was performed according to the grading standard of the degree of synovial tissue disease. Enzyme-linked immunosorbent assay (ELISA) was applied to verify the efficacy of moxibustion in reducing inflammation. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of the TIM-3/TLR4-MyD88-NF-κB signaling pathway-related molecules, and Western blot was used to detect the contents of synovial NF-κB.

RESULTS: We established the Freund's complete adjuvant (FCA)-induced RA model in rats. The expression level of M1 polarization signaling pathway TLR4-MyD88-NF-κB and the inflammatory factors interleukin-12(IL-12), tumor necrosis factor alpha (TNF-α), and tumor necrosis factor beta (TNF-β) were significantly increased in the RA model. After moxibustion treatment, the expression level of TLR4-MyD88-NF-κB was significantly decreased, and the inflammatory factors IL-12, TNF-α, and TNF-β were decreased, but the expression level was significantly increased in the RA model. When TIM-3 expression was inhibited, the expression level of TLR4-MyD88-NF-κB, and the inflammatory factors IL-12, TNF-α, and TNF-β were not suppressed, even after moxibustion treatment.

CONCLUSIONS: Moxibustion regulates the key target TIM-3 by acting on the Zusanli (ST36) and Shenshu (BL23) points, thereby inhibiting the M1 polarization of macrophages; that is, it inhibits the TLR4-MyD88-NF-κB signaling pathway, and finally achieves alleviation of pathological changes and anti-inflammatory effects.

Key words: moxibustion, arthritis, rheumatoid, TIM-3, macrophage polarization, toll-like receptor 4, myeloid differentiation factor 88, nuclear factor kappa B, signal transduction

LUO Kun, ZHONG Yumei, GUO Yanding, ZHANG Linlin, HU Danhui, MA Wenbin, YANG Xin, ZHOU Haiyan. Moxibustion inhibits the macrophage M1 polarization toll-like receptor 4/myeloid differentiation factor 88/nuclear factor kappa B signaling pathway by regulating T-cell immunoglobulin and mucin-containing protein-3 in rheumatoid arthritis[J]. Journal of Traditional Chinese Medicine, 2024, 44(6): 1227-1235.

Figures/Tables 5

Figure 1 Investigation of the effect of moxibustion on reducing foot swell and inflammatory responses in rats with rheumatoid arthritis A: photo of footpads of rats in the control group; B: photo of footpads of rats in the rheumatoid arthritis group; C: photo of footpads of rats in the moxibustion group; D: HE stained image of ankle of control groups, magnification:× 20; E: HE stained image of ankle of rheumatoid arthritis groups, magnification:× 20; F: HE stained image of ankle of moxibustion groups, magnification:× 20; G: HE stained image of ankle of control groups, magnification:× 200; H: HE stained image of ankle of rheumatoid arthritis groups, magnification:× 200; I: HE stained image of ankle of moxibustion groups, magnification:× 200. The control group received 0.5 mL/kg of saline with bilateral foot pads; the rheumatoid arthritis group received 0.5 mL/kg of FCA with bilateral foot pads; the moxibustion group received 0.5 mL/kg of FCA with bilateral foot pads for three cycles of moxibustion treatment. HE: hematoxylin-eosin staining; FCA: Freund's Adjuvant Complete.

Table 1 Thicknesses of the left and right foot pads (cm, $\bar{x}±s$)

Item	Group	n	Day 0	Day 7	Day 14	Day 21	Day 28
Right	Control	6	0.35±0.03	0.35±0.03	0.34±0.02	0.33±0.02	0.34±0.02
	RA	6	0.37±0.03	0.63±0.02^a	0.66±0.05^a	0.62±0.04^a	0.59±0.03^a
	Mox	6	0.37±0.02	0.62±0.03^a	0.51±0.04^ab	0.49±0.05^ab	0.50±0.02^ab
Left	Control	6	0.36±0.02	0.39±0.02	0.36±0.03	0.36±0.03	0.36±0.02
	RA	6	0.37±0.03	0.71±0.12^a	0.69±0.10^a	0.71±0.08^a	0.68±0.06^a
	Mox	6	0.37±0.02	0.71±0.03^a	0.55±0.04^ab	0.52±0.02^ab	0.52±0.03^ab

Figure 2 Inflammatory responses in rats with RA can be improved by moxibustion A: levels of IFN-γ in serum of rats in each group; B: levels of IL-6 in serum of rats in each group; C: levels of MHC-Ⅱ in serum of rats in each group; D: levels of MMP-1 in serum of rats in each group. The rheumatoid arthritis and moxibustion groups injected 0.5 mL/kg of FCA, the control group received an equal amount of normal saline, and three cycles of moxibustion treatment for the moxibustion group. IFN-γ: interferon gamma; IL-6: interleukin-6; MHC-Ⅱ: major histocompatibility complex Ⅱ; MMP-1: matrix metallopeptidase 1; FCA: Freund's Adjuvant Complete. The Data represent the mean ± standard deviation using one-way analysis of variance (n = 6). aP < 0.05 vs the control group; bP < 0.05 vs the rheumatoid arthritis group.

Figure 3 Moxibustion inhibits M1 polarization of macrophages. Expression of factors related to TLR4-MyD88-NF-κB pathway A: expression of TLR4mRNA; B: expression of MyD88mRNA. C: Western blot results showing expression level of NF-κB protein; D: Western blot analysis; E: expression of TIM-3mRNA; F: expression of TIM-3mRNA after lentivirus interference. qPCR was performed on spleens from rheumatoid arthritis rats to determine mRNA expression levels. Measurement of NF-κB expression in synovium by Weston blot. The rheumatoid arthritis, moxibustion groups and TIM-3 lentiviral intervention groups injected 0.5 mL/kg of FCA, the control group received an equal amount of normal saline, and three cycles of moxibustion treatment for the moxibustion group. Lentiviral was injected into the rat foot pads of the TIM-3 lentiviral intervention group. TLR4: Toll-like receptor 4; MyD88: Myeloid differentiation factor 88; NF-κB: Nuclear factor kappa B; TIM-3: T-cell immunoglobulin and mucin-containing protein-3. The Data represent the mean ± standard deviation using one-way analysis of variance (n = 6). aP < 0.01, cP < 0.05 vs the control group; bP < 0.01, dP < 0.05 vs the rheumatoid arthritis group.

Figure 4 Moxibustion modulates TIM-3 to inhibit macrophage M1 polarization Expression of factors related to Tim-3/TLR4-MyD88-NF-κB pathway. A: levels of IL-12 in serum of rats in each group; B: Levels of TNF-α in serum of rats in each group; C: levels of TNF-β in serum of rats in each group; D: expression of MyD88mRNA; E: expression of NF-κBmRNA. The rheumatoid arthritis, moxibustion groups, TIM-3 lentiviral intervention and TIM-3 lentiviral intervention + moxibustion intervention groups injected 0.5 mL/kg of FCA, the control group received an equal amount of normal saline, and three cycles of moxibustion treatment for the moxibustion and TIM-3 lentiviral intervention + moxibustion intervention groups. Lentiviral was injected into the rat foot pads of the TIM-3 lentiviral intervention and TIM-3 lentiviral intervention + moxibustion intervention groups. IL-12: interleukin-12; TNF-α: tumor necrosis factor alpha; TNF-β: tumor necrosis factor beta; MyD88: Myeloid differentiation factor 88; NF-κB: Nuclear factor kappa B; TIM-3: T-cell immunoglobulin and mucin-containing protein-3; FCA: Freund's Adjuvant Complete. The Data represent the mean ± standard deviation using one-way analysis of variance (n = 6). aP < 0.01, dP < 0.05 vs the control group; bP < 0.01, cP < 0.05 vs the rheumatoid arthritis group.

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Moxibustion inhibits the macrophage M1 polarization toll-like receptor 4/myeloid differentiation factor 88/nuclear factor kappa B signaling pathway by regulating T-cell immunoglobulin and mucin-containing protein-3 in rheumatoid arthritis

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