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Supplemental material, sj-docx-1-aim-10.1177_09645284221085278 for Manual acupuncture at ST36 attenuates rheumatoid arthritis by inhibiting M1 macrophage polarization and enhancing Treg cell populations in adjuvant-induced arthritic rats by Nannan Yu, Fuming Yang, Xue Zhao, Yongming Guo, Yuan Xu, Guangchang Pang, Yinan Gong, Shenjun Wang, Yangyang Liu, Yuxin Fang, Kun Yu, Lin Yao, Hui Wang, Kuo Zhang, Baohu Liu, Zhenguo Wang, Yi Guo and Zhifang Xu in Acupuncture in Medicine

Wei Li,1 Yinan Gong,1 Jingyi Liu,1 Yongming Guo,1– 3 Huiling Tang,1 Siru Qin,1 Yadan Zhao,1 Songtao Wang,1 Zhifang Xu,1– 3 Bo Chen1– 3 1Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China; 2School of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People’s Republic of China; 3National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300381, People’s Republic of ChinaCorrespondence: Zhifang XuSchool of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, No. 10 Poyang Lake Road, Tuanbo New Town, Jinghai District, Tianjin, 301617, People’s Republic of ChinaTel +86-22-5959-6290Fax +86-22-2748-5189Email xuzhifangmsn@hotmail.comBo ChenSchool of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, No. 10 Poyang Lake Road, Tuanbo New Town, Jinghai District, Tianjin, 301617, People’s Republic of ChinaTel +86-22-5959-6290Fax +86-22-2748-5189Email tjutcmchenbo@163.comAbstract: Chronic low back pain (CLBP), lasting > 3 months, is the end result of multiple pathogenic factors. Unfortunately, little is known about CLBP pathogenesis, which limits its advancements in clinical therapy and disease management. This paper summarizes the known pathological axes of CLBP, involving both peripheral and central systems. In particular, this paper details injurious nerve stimulation, inflammation-induced peripheral pathway, and central sensitization. Lumbar components, such as intervertebral disc (IVD), facet joints, muscles, fascia, ligaments, and joint capsules, contain pain receptors called nociceptors. Degeneration of the aforementioned lumbar components activates inflammatory pathways, which can directly damage nerves, lower nociceptor threshold to fire action potentials (AP), and cause pain. Additionally, damaged lumbar IVDs and endplates can also lead to the pathologic invasion of nerve growth and innervation, followed by the compression of herniated IVDs on nerve roots, thereby causing traumatic neuropathic pain. The central mechanism of CLBP involves alteration of the sensory processing of the brain and malfunction of the descending pain modulatory system, which facilitates pain amplification in the center nervous system (CNS). Lastly, abnormalities in the brain biochemical metabolism, activation of glial cells, and subsequent inflammation also play important roles in CLBP development. Taken together, inflammation plays an important role in both peripheral and central sensitization of CLBP. Due to the heterogeneity of CLBP, its pathological mechanism remains complex and difficult to understand. Therefore, it is a worthy field for future research into the subcomponents of CLBP pathogenesis, in order to distinguish the specific form of the disease, identify its origins, and develop corresponding highly effective comprehensive therapy against CLBP.Keywords: chronic low back pain, inflammation, degeneration, nerve innervation, central sensitization

Although pain is regarded as a global public health priority, analgesic therapy remains a significant challenge. Pain is a hypersensitivity state caused by peripheral and central sensitization, with the latter considered the culprit for chronic pain. This study summarizes the pathogenesis of central sensitization from the perspective of neuroglial crosstalk and synaptic plasticity and underlines the related analgesic mechanisms of acupuncture. Central sensitization is modulated by the neurotransmitters and neuropeptides involved in the ascending excitatory pathway and the descending pain modulatory system. Acupuncture analgesia is associated with downregulating glutamate in the ascending excitatory pathway and upregulating opioids, 𝛾-aminobutyric acid, norepinephrine, and 5-hydroxytryptamine in the descending pain modulatory system. Furthermore, it is increasingly appreciated that neurotransmitters, cytokines, and chemokines are implicated in neuroglial crosstalk and associated plasticity, thus contributing to central sensitization. Acupuncture produces its analgesic action by inhibiting cytokines, such as interleukin-1β, interleukin-6, and tumor necrosis factor-α, and upregulating interleukin-10, as well as modulating chemokines and their receptors such as CX3CL1/CX3CR1, CXCL12/CXCR4, CCL2/CCR2, and CXCL1/CXCR2. These factors are regulated by acupuncture through the activation of multiple signaling pathways, including mitogen-activated protein kinase signaling (e.g., the p38, extracellular signal-regulated kinases, and c-Jun-N-terminal kinase pathways), which contribute to the activation of nociceptive neurons. However, the responses of chemokines to acupuncture vary among the types of pain models, acupuncture methods, and stimulation parameters. Thus, the exact mechanisms require future clarification. Taken together, inhibition of central sensitization modulated by neuroglial plasticity is central in acupuncture analgesia, providing a novel insight for the clinical application of acupuncture analgesia.