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Journal of Traditional Chinese Medicine >

2026 , Vol. 46 >Issue 4: 844 - 853

DOI: https://doi.org/10.19852/j.cnki.jtcm.20251201.001

Original Articles

Regulatory effects and mechanisms of the acupuncture-induced complement component 1q on the high mobility group box 1 -receptor for advanced glycation end products-nuclear factor kappa-B pathway at Zusanli (ST36)

  • KANG Xiaochun ,
  • WU Sinuo ,
  • LI Ningcen ,
  • XU Wenyue ,
  • XU Zhifang ,
  • Thong Yikchih ,
  • LI Peiyun ,
  • TU Shiwei ,
  • MA Ning ,
  • LI Yanwei ,
  • DOU Baomin ,
  • TAN Wenjun ,
  • GUO Jing ,
  • GUO Yi ,
  • PAN Xingfang ,
  • Lü Zhongxi
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  • 1 School of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
    2 Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; School of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
    3 Institute of Traditional Chinese Medicine, Suzuka University of Medical Science, Suzuka 5100226, Japan
    4 Key Laboratory of Intelligent Computing in Medical Image, Ministry of Education, Northeastern University, Shenyang 110189, China
    5 School of Automation, Guangdong University of technology, Guangzhou 510006, China
KANG Xiaochun and WU Sinuo are co-first authors and contributed equally to this work

Received date: 2025-05-10

  Accepted date: 2025-09-30

  Online published: 2025-12-01

Supported by

National Key R&D Program of China: Efficacy and Safety Verification of Intelligent Traditional Chinese Medicine Acupuncture Robot System(2022YFB4703100);National Natural Science Foundation of China: Study on the Effect and Mechanism of C1q Protein in the Ordered and Controlled Inflammatory Response in Acupuncture Area(82105023);Mechanism of electroacupuncture-driven Surface-modified Graded Cell-derived Glycosylated Exo-miR-146a targeting T Cell Immunoglobulin and Mucin Domain-containing Protein 3 to Regulate Exhausted T Cells and Alleviate Sepsis Immunosuppression(82305370);Initial Dynamic Regulation Mechanism of Acupuncture Effect via Physicochemical Coupling Network in Acupoint Microenvironment(82030125);Young Elite Scientists Sponsorship Program by China Association of Chinese Medicine: Initiation Mechanism of Acupuncture Analgesia Mediated by High Mobility Group Box 1 at Acupoints(2023-QNRC2-B04)

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Abstract

OBJECTIVE: To investigate what are the crucial regulators and mechanisms involved in regulating the inflammatory responses at Zusanli (ST36).

METHODS: Initially, we utilized enzyme-linked immunosorbent assay (ELISA) to detect the variations of high mobility group box 1 (HMGB1), interleukin-10 (IL-10), and complement component 1q (C1q) concentrations at Zusanli (ST36) on day 1 (D1), day 3 (D3), day 5 (D5) and day 7 (D7) after acupuncture to clearly depict the time-dependent changes of these inflammatory substances. Subsequently, we utilized C1qa-knockout (C1qa-KO) mice to investigate the role of acupuncture-induced C1q in inflammatory responses at Zusanli (ST36). We utilized hematoxylin and eosin staining to observe the inflammatory morphological alterations, examined the activation of the NF-κB pathway by immunofluorescence and assessed HMGB1 and IL-10 changes using ELISA. Lastly, to uncover the specific mechanism by which C1q regulates the acupuncture-induced inflammatory responses at Zusanli (ST36), we employed Western blot (WB) to measure the expression levels of receptor of advanced glycation end products (RAGE), leukocyte associated immunoglobulin like receptor 1 (LAIR-1), and src homology region 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) proteins and used immunofluorescence to detect the polarization of classically activated macrophages (M1) and alternatively activated macrophages (M2).

RESULTS: Compared with the wild-type group, the levels of HMGB1 and C1q of acupuncture (ACU) group at Zusanli (ST36) were increased on D3 after acupuncture, while the level of IL-10 decreased. With continued higher level of HMGB1, both C1q and IL-10 level were increased on D7. After knocking out C1q, compared with the ACU group, the C1qa-KO+acupuncture (C1q-/-+ACU) group exhibited further aggravated inflammatory infiltrations in the epidermal layer, dermal layer, and muscular layer. At Zusanli (ST36), the level of HMGB1 was further increased, accompanied by an intensified activation of the NF-κB pathway. Meanwhile, the level of IL-10 exhibited a downward tendency, which jointly led to the exacerbation of inflammatory responses at Zusanli (ST36). In comparison with the ACU group, the C1q-/-+ACU group showed a reduction in SHP-1 levels, a downward tendency of LAIR-1 expression, whereas the expression of RAGE exhibited an upward inclination. Furthermore, the number of M1 macrophages at Zusanli (ST36) increased significantly, in stark contrast to a pronounced decline in the number of M2 macrophages.

CONCLUSION: Zusanli (ST36) acupuncture initiates a time-regulated inflammatory cascade might through the following mechanism: HMGB1 release (D1) triggers C1q upregulation (D3), culminating on D7 with C1q binding to LAIR-1, which recruits SHP-1 to inhibit HMGB1-RAGE-NF-κB signaling viaM2 polarization and IL-10 feedback, ensuring precisely controlled inflammation at acupoints.

Key words： acupuncture; HMGB1 protein; receptor for advanced glycation end products; NF-kappa B; complement C1q; inflammatory response regulation; sequential and controllable

Cite this article

KANG Xiaochun , WU Sinuo , LI Ningcen , XU Wenyue , XU Zhifang , Thong Yikchih , LI Peiyun , TU Shiwei , MA Ning , LI Yanwei , DOU Baomin , TAN Wenjun , GUO Jing , GUO Yi , PAN Xingfang , Lü Zhongxi . Regulatory effects and mechanisms of the acupuncture-induced complement component 1q on the high mobility group box 1 -receptor for advanced glycation end products-nuclear factor kappa-B pathway at Zusanli (ST36)[J]. Journal of Traditional Chinese Medicine, 2026 , 46(4) : 844 -853 . DOI: 10.19852/j.cnki.jtcm.20251201.001

References

1. Lyu ZX, Guo YM, Gong YN, et al. The role of neuroglial crosstalk and synaptic plasticity-mediated central sensitization in acupuncture analgesia. Neural Plast 2021; 2021: 1-18.
2. Gong YN, Li NC, Lü ZX, et al. The neuro-immune microenvironment of acupoints-initiation of acupuncture effectiveness. J Leukoc Biol 2020; 108: 189-98.
3. Park JY, Park JJ, Jeon S, et al. From peripheral to central: the role of ERK signaling pathway in acupuncture analgesia. J Pain 2014; 15: 535-49.
4. Qu F, Cui YR, Zeng J, et al. Acupuncture induces adenosine in fibroblasts through energy metabolism and promotes proliferation by activating MAPK signaling pathway via adenosine(3) receptor. J Cell Physiol 2020; 235: 2441-51.
5. Zhang K, Zhao X, Yang T, et al. Initiation of acupoint molecular mechanisms for manual acupuncture analgesia-nuclear factor κB signaling pathway. Chin J Integr Med 2021; 27: 933-9.
6. Agalave NM, Svensson CI. Extracellular high-mobility group box 1 protein (HMGB1) as a mediator of persistent pain. Mol Med 2015; 20: 569-78.
7. Xi Q, Cui R, Jing G, Guo YM. A preliminary study on the role of local TLR4 in acupoint in the local inflammatory response after acupuncture. Tianjin Zhong Yi Yao 2015; 32: 88-92.
8. Ding N, Wang F, Xiao H, Xu LX, She SZ. She S. Mechanical ventilation enhances HMGB1 expression in an LPS-induced lung injury model. Plos One 2013; 8: e74633.
9. Ghebrehiwet B, Hosszu KK, Valentino A, Peerschke EI. The C1q family of proteins: insights into the emerging non-traditional functions. Front Immunol 2012; 3; 52.
10. Noble M, Pr?schel C. The many roles of C1q. Elife 2020; 9: e61599.
11. Son M, Porat A, He MZ, et al. C1q and HMGB1 reciprocally regulate human macrophage polarization. Blood 2016; 128: 2218-28.
12. Fraser DA, Arora M, Bohlson SS, Lozano E, Tenner AJ. Generation of inhibitory NFkappaB complexes and phosphorylated cAMP response element-binding protein correlates with the anti-inflammatory activity of complement protein C1q in human monocytes. J Biol Chem 2007; 282: 7360-7.
13. Son M. Understanding the contextual functions of C1q and LAIR-1 and their applications. Exp Mol Med 2022; 54: 567-72.
14. Zhang K, Zhao X, Ding SS, et al. Applying complex network and cell-cell communication network diagram methods to explore the key cytokines and immune cells in local acupoint involved in acupuncture treating inflammatory pain. Evid Based Complement Alternat Med 2020; 2020: 2585960.
15. Li YM. In the search of mobile target for acupuncture: why is mast cell? Zhong Guo Zhen Jiu 2021; 41: 965-70.
16. Wang ZG, Yi T, Long M, et al. Electro-acupuncture at Zusanli acupoint (ST36) suppresses inflammation in allergic contact dermatitis via triggering local IL-10 production and inhibiting p38 MAPK activation. Inflammation 2017; 40: 1351-64.
17. Kolev M, Le Friec G, Kemper C. Complement-tapping into new sites and effector systems. Nat Rev Immunol 2014; 14: 811-20.
18. Fraser DA, Bohlson SS, Jasinskiene N, et al. C1q and MBL, components of the innate immune system, influence monocyte cytokine expression. J Leukoc Biol 2006; 80: 107-16.
19. Spivia W, Magno PS, Le P, Fraser DA. Complement protein C1q promotes macrophage anti-inflammatory M2-like polarization during the clearance of atherogenic lipoproteins. Inflamm Res 2014; 63: 885-93.
20. Benoit ME, Clarke EV, Morgado P, Fraser DA. Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells. J Immunol 2012; 188: 5682-93.
21. Son M, Santiago-Schwarz F, Al-Abed Y. C1q limits dendritic cell differentiation and activation by engaging LAIR-1. Proc Natl Acad Sci U S A 2012; 109: E3160-67.
22. Wen LZ, Ding K, Wang ZR, et al. SHP-1 acts as a tumor suppressor in hepatocarcinogenesis and HCC progression. Cancer Res 2018; 78: 4680-91.
23. Pesce M, Franceschelli S, Ferrone A, et al. The NF-kB regulates the SHP-1 expression in monocytes in congestive heart failure. Front Biosci (Landmark Ed) 2017; 22: 757-71.
24. Takagane K, Umakoshi M, Itoh G, Kuriyama S, Goto A, Tanaka M. SKAP2 suppresses inflammation-mediated tumorigenesis by regulating SHP-1 and SHP-2. Oncogene 2022; 41: 1087-99.
25. Deng DL, Xu F, Ma LL, et al. Electroacupuncture alleviates CFA-induced inflammatory pain via PD-L1/PD-1-SHP-1 pathway. Mol Neurobiol 2023; 60: 2922-36.
26. Rojas A, Delgado-López F, Perez-Castro R, et al. HMGB1 enhances the protumoral activities of M2 macrophages by a RAGE-dependent mechanism. Tumour Biol 2016; 37: 3321-9.
27. Liu TY, Xiang A, Peng T, et al. HMGB1-C1q complexes regulate macrophage function by switching between leukotriene and specialized proresolving mediator biosynthesis. Proc Natl Acad Sci USA 2019; 116: 23254-63.
28. Xu Y, Hong SH, Zhao X, et al. Acupuncture alleviates rheumatoid arthritis by immune-network modulation. Am J Chin Med 2018; 46: 997-1019.
29. Saraiva M, O'Garra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol 2010; 10: 170-81.
30. Van Beijnum JR, Buurman WA, Griffioen AW, Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1). Angiogenesis 2008; 11: 91-9.
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