TYPE Review

PUBLISHED 06 April 2023

DOI 10.3389/fimmu.2023.1147718

The immunomodulatory
OPEN ACCESS mechanisms for
EDITED BY
Vijay Kumar,
Louisiana State University, United States
acupuncture practice
REVIEWED BY
Salvador Quiroz-González, Meng Wang, Weili Liu, Jiayi Ge and Shenbin Liu*
Universidad Estatal del Valle de Ecatepec,
Mexico State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of
Archana Saxena, Brain Science, Huashan Hospital, Fudan University, Shanghai, China
University of South Carolina, United States

*CORRESPONDENCE
Shenbin Liu
[email protected] The system physiology approaches that emerge in western countries in recent
SPECIALTY SECTION years echo the holistic view of ancient Traditional Chinese Medicine (TCM)
This article was submitted to practices that deal with the root, rather than only the symptoms of diseases.
Inflammation,
a section of the journal Particularly, TCM practices, including acupuncture, emphasize the mobilization
Frontiers in Immunology of self-healing mechanisms to bring back body homeostasis. Acupuncture has
RECEIVED 20 January 2023 been practiced for over two thousand years to modulate body physiology via
ACCEPTED 20 March 2023 stimulation at specific body regions (acupoints). With the development of various
PUBLISHED 06 April 2023
research on acupuncture therapy, its regulatory effect on the immune system
CITATION has been gradually recognized, especially on immunological diseases,
Wang M, Liu W, Ge J and Liu S (2023) The
immunomodulatory mechanisms for
including infectious and allergic diseases. In this study, we reviewed the
acupuncture practice. immunomodulatory mechanism of acupuncture and systematically integrates
Front. Immunol. 14:1147718. existing research to respectively elucidate the modulatory mechanisms of
doi: 10.3389/fimmu.2023.1147718
acupuncture on the innate immune system, adaptive immune system, and
COPYRIGHT
© 2023 Wang, Liu, Ge and Liu. This is an
well-known neuroanatomical mechanisms, including intact somatosensory-
open-access article distributed under the autonomic reflex pathway. With the advances made in recent systems
terms of the Creative Commons Attribution physiology studies, we now have a great opportunity to gain insight into how
License (CC BY). The use, distribution or
reproduction in other forums is permitted, acupuncture modulates immunity, and subsequently improves its efficacy.
provided the original author(s) and the
copyright owner(s) are credited and that
KEYWORDS
the original publication in this journal is
cited, in accordance with accepted acupuncture, immune system, neuro-immune regulation, autonomic nervous system,
academic practice. No use, distribution or HPA axis
reproduction is permitted which does not
comply with these terms.

Abbreviations: IBS, Inflammatory Bowel Syndrome; MCs, Mast Cells; TCM, Traditional Chinese Medicine;
MA, Manual Acupuncture; CFA, Complete Freund’s ; djuvant; AIA, Adjuvant-Induced Arthritics; EA,
Electroacupuncture; LFES, Low-Frequency Electrical Stimulation; NK cells, Nature Killer Cells; CNS, Central
Nervous System; AD, Alzheimer’s Disease; PD, Parkinson’s Disease; TBI, Traumatic Brain Injury; Tfh cells, T
follicular helper cells; Treg cells, Regulatory T cells; BALF, Bronchoalveolar Lavage Fluid; CAIP, Cholinergic
Anti-inflammatory Pathway; BGA, Brain-Gut Axis; ENS, Enteric Nervous System; ANS, Autonomic Nervous
System; 5-HT, 5-Hydroxytryptamine; HPA axis, Hypothalamus-Pituitary-Adrenal Axis; DRG, Dorsal Root
Ganglia; CG, Celiac Ganglia; DA, Dopamine; NE, Norepinephrine; DMV, Dorsal Motor Nucleus of Vagus;
NTS, Nucleus of the Solitary Tract.

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1 Introduction mechanisms of acupuncture in immunomodulation, including

intact autonomic reflex pathways. This is of great significance to
Acupuncture practice is one of the most popular forms of the popularization of acupuncture as a medical practice.
alternative and complementary medicine in the world. As a
medical practice with roots in China, it has been widely applied
for more than three thousand years and has amassed a wealth of 2 Acupuncture modulates innate
clinical and theoretical evidence. Today, acupuncture practice has immune cells’ activity
already received considerable attention. Acupuncture exerts the
therapeutic effect via stimulating specific sites on the body surface 2.1 Mast cells
(which we called acupoints). The main methods of stimulation
include manual acupuncture, electroacupuncture, and Mast cells (MCs), are the tissue-resident immune effector cells
transcutaneous acupoint electrical stimulation. Acupuncture and the innate immune system’s first line of defense. They react to a
practice is widely used to alleviate or cure various diseases, range of environmental physical stimuli, such as temperature,
including endocrine and metabolic diseases, mental and pressure, pathogens, trauma, and acupuncture. When exposed to
behavioral disorders, neurological disorders, diseases of the various stimuli, they release strong biological mediators into the
circulatory system, cutaneous disorders, diseases of tissues around them, triggering an inflammatory reaction that aids
musculoskeletal and connective tissue and so on (1). The whole in the healing of wounds and the removal of infections (9). MCs are
process is non-invasive and safe. According to recent systematic the primary initiators and regulators of inflammatory and other
reviews, acupuncture is a safe and low-cost treatment with minimal immune responses that are widely distributed in connective tissue,
side effects. Till now, none of the randomized controlled trials and they largely interact with the external environment close to
included in these systematic reviews reported life-threatening blood vessels and sensory nerves (10). According to pertinent
adverse events (2, 3). With the stable, repeatable, and quantifiable research, MCs are dispersed along the direction of blood arteries
effect, acupuncture practice has become commonly accepted and and nerves and enriched close to acupoints in model organisms like
studied. As early as 1997, the NIH issued a consensus statement on rats and humans. To provide analgesic and anti-inflammatory
the effectiveness and scientific nature of acupuncture therapy. Until effects, MCs also take part in the nerve transduction process in
now, more than 3 million American adults have used acupuncture response to sensory signals from the surface of the body.
therapy to control chronic pain, which is the most common reason The link between the distribution of MCs on the body’s surface
for seeking acupuncture treatment, and the analgesic and anesthetic and the TCM concept of acupoints can be seen obviously. The
effects of acupuncture are no longer in doubt (4–6). acupoints are considered to be dynamic composite structures
Accumulated evidence showed the potential of acupuncture in composed of MCs, nerve fibers, and vascular structures. MCs
the treatment of immune system diseases caused by immune were found to be densely distributed around the rat acupoints
system defects. Acupuncture has been demonstrated to regulate and blood vessels and were visible via contemporary methods like
the immune system of the body and correct pathological histological methods. Electroacupuncture (EA) stimulation
conditions, thereby providing effective relief or treatment of encourages the recruitment and migration of MCs along blood
associated diseases. For instance, acupuncture has been shown vessels and nerves (11, 12). The distribution pattern of MCs was
to modulate systemic inflammatory responses, resulting in a highly correlated with the distribution of 14 classic acupoints in the
significant improvement in survival rates among mice with fatal meridians, suggesting that MCs may be a tissue target of
sepsis (7). In addition, acupuncture has also been shown to be acupuncture and moxibustion stimulation. Li et al. quantified the
effective in the treatment of inflammatory bowel syndrome (IBS), number and density of skin in different parts of the body using skin
mainly by modulating inflammation-related cytokines and biopsies, dermal cell counts, etc (13). Preliminary histological
immune cell differentiation in vivo, reducing inflammatory evidence of acupuncture neuro-immunomodulation can be
responses and clinical symptoms (8). obtained by combining these pertinent investigations.
Acupuncture has a promising future as a kind of safe and efficient It is commonly accepted that acupuncture may stimulate
medical practice to modulate the body’s immune system. Since afferent neurons to conduct upward and trigger receptors on the
acupuncture is based on a system that is distinct from modern body’s surface. Acupuncture can activate MCs, which are a key
Western medicine, current research is focusing on the role of component of acupoints, through Transient receptor potential
acupuncture and the associated neurobiological mechanisms. In vanilloid 2 (TRPV2) channels, which subsequently act on
recent decades, a series of breakthroughs in the understanding of histamine H1 and adenosine A1 receptors to transform
the modulatory mechanism of acupuncture has been made due to the mechanical inputs into neurological impulses that go upward
rapid advancement of biological techniques. The specific (14). The conclusion that MC stabilizers can suppress this
neuroregulatory mechanisms of acupuncture are no longer a black neurological communication, provides that at least some of
box. Herein, we reviewed the immunomodulatory mechanism of acupuncture’s effects are influenced by MCs activity (11).
acupuncture, and systematically integrated the existing research Following acupuncture, MCs moved to the local acupoints
results to elucidate the regulation of acupuncture on the innate and through the blood arteries of the subdermal and subcutaneous
adaptive immune response, and the well-known neuroanatomy tissues, and the aggregated MCs produced more tryptase through

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degranulation, histamine, and 5-hydroxytryptamine (5-HT) (15– In addition to anti-inflammatory and analgesic effects,
17). The nerve fibers also released more substance P and calcitonin acupuncture has been demonstrated to play a role in tissue repair
gene-related peptide P (CGRP). Additionally, it has been found that by regulating macrophages. The recovery phase of muscle injury
MC activation can result in the production of adenosine includes several stages of degeneration, inflammation, regeneration,
triphosphate (ATP), which functions as the primary mediator of and fibrosis, with macrophages acting as the primary orchestrator
acupuncture-induced analgesia through binding to purinoreceptor throughout the process (27). Large numbers of macrophages
receptors (18). infiltrate the injury site during the post-injury inflammatory
It may be presumed that there are connections or information phase, and during the post-inflammatory tissue regeneration
transfers between MCs and nerve terminals that are given the role phase, macrophages control tissue repair by flipping to distinct
that MCs play in nerve conduction. The presence of “Synaptic” phenotypes (28). Yan et al. in establishing a rat model of skeletal
connections between MCs and nerve terminals has been muscle injury, EA was applied to ST36 (29). The findings revealed
investigated preliminarily, with immunohistochemistry providing that the EA group’s secretion of IL-4, IL-13, and interferon (IFN)-g
neuroanatomical proof for the control of the neurological immune was greatly enhanced. IFN-g was secreted less often, and there were
system (19, 20). Further research is necessary to gain a better more M2-type macrophages present, which expedites the repair of
u n d e r s t an d i n g o f t h e m e c h an i s m o f M C s i n n e u r o- skeletal muscle injury.
immunomodulation induced by acupuncture. As previously mentioned, macrophages control the
inflammatory-anti-inflammatory balance in vivo through
phenotypic flipping, as was previously mentioned. In a study by
2.2 Macrophages Hu et al. (30), Low-frequency electrical stimulation (LFES) of GB34
(Yanglingquan, Gallbladder 34) and ST36 acupoints helped prevent
As an essential element of innate immunity, macrophages muscle atrophy by generating a brief inflammatory response in a rat
provide the first line of defense against pathogens (21). model of CKD-induced skeletal muscle atrophy. After day 3, pro-
Macrophages fulfill their roles by modulating cell division and inflammatory M1 macrophage levels in muscle tissue started to
tissue repair, typically polarizing different phenotypes to obtain decline during the early phase of stimulation, whereas anti-
distinct functional phenotypes. Traditional macrophage M1 inflammatory M2 macrophage levels started to rise. Acupuncture
activation and alternative M2 activation are the two extremes of may play a role in preserving homeostasis by controlling
their phenotypic alterations. M1 macrophages release cytokines that macrophages. Since insulin-like growth factor (IGF)-1, which is
prevent neighboring cells from proliferating and breaking down mostly produced by macrophages, is up-regulated to enhance
nearby tissues, while M2 macrophages release cytokines that protein metabolism and encourage the synthesis of muscle.
encourage neighboring cells to proliferate and repair nearby
tissues. The heterogeneity of the macrophage phenotype is
controlled by many physiological and pathological states, as well 2.3 Neutrophils
as environmental influences (22). Studies have revealed that
acupuncture primarily controls the polarization of M1/M2 by The neutrophil is myeloid leukocytes and is one of the main
modifying the production of cytokines related to inflammation effector cells of the innate immune response. It can regulate the
and its re-recruitment at the site of inflammatory injury, which body’s immune response, such as acute injury and repair process,
improves the anti-inflammatory effect, to reduce inflammatory pain chronic inflammation process, and so on, mainly through the
and tissue repair. recruitment and infiltration of infected and damaged tissues,
Zhang et al. treated the complete Freund’s Adjuvant (CFA)- recognition and phagocytosis of microorganisms, killing
induced inflammatory pain rats with manual acupuncture (MA), pathogens, and making a difference (31). Therefore, the
and they found that the inflammatory pain was significantly enrichment of neutrophils is often regarded as a marker and
relieved, and the amounts of macrophages at acupoints were also biological indicator of acute infection injury. Today, in addition
raised in the experimental group (23). Interleukin (IL)-6, monocyte to its role in acute infection, the role of neutrophils in the
chemoattractant protein (MCP)-1, and IL-1 are important maintenance of immune homeostasis has also been much
cytokines that have been identified by statistical and cytokine studied (32).
association networks. These cytokines are also primarily secreted Neutrophils are produced daily in the bone marrow and
by macrophages (24, 25). This shows that the onset of the analgesic makeup 50-70% of all circulating white blood cells in humans.
action of MA on inflammatory pain is mediated by macrophages at They are synthesized and converted rapidly, especially during
acupoints. Yang et al. found that Adjuvant-induced arthritics (AIA) periods of inflammation and immune imbalance in the body (33).
had considerable analgesic and anti-inflammatory effects after MA So, when acupuncture regulates the immune function of the body, it
therapy (26). It is believed that the anti-inflammatory effect of MA is often accompanied by the regulation of the quantity and activity
may be realized by preventing the polarization of the M1 phenotype of neutrophils. A small clinical study showed that acupuncture can
because M1 macrophages were suppressed, IL-1 levels were improve the immune protection of ovarian cancer patients due to
decreased, and the immune cell communication network was chemotherapy-induced immune suppression caused by the
inhibited at the ST36 (Zusanli, Stomach 36) location. reduction of white blood cell count (34). Another animal study

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found that acupuncture significantly improved survival in septic 2.5 Astrocytes and microglia
rats, by reversing the migration of neutrophil injury to the
peritoneal cavity (35). Zhang et al. demonstrated that, in a mouse Astrocytes are neuroglia derived from neuroectoderm and
model of left anterior descending (LAD) coronary artery ligation to neural progenitors, which are abundant in the central nervous
mimic myocardial injury, acupuncture inhibited the activation of system (CNS) and play essential functions in the CNS of healthy
the NLRP3 inflammasome, promoting macrophage M2 and diseased organisms. During CNS injury or infection, many
polarization, and reducing the recruitment of neutrophils in the changes in astrocytes’ morphology, molecular expression, and
damaged myocardium, thereby reducing infarct size and improving function affect the progress of various CNS diseases (48). The
cardiac function (36). microglia are a type of important immune cell in the CNS. It is
similar to tissue-resident macrophages in molecular morphology
and biology. It can be divided into pro-inflammatory type M1 and
2.4 Natural killer (NK) cells anti-inflammatory type M2. The dual immunomodulatory effect of
which is mainly realized through the transformation of its
NK cells, the body’s third lymphocyte after T and B cells, are the phenotype (49). In the early stages of injury, M1 is polarized,
primary effector cells in the innate immune system. They can secreting high levels of pro-inflammatory factors such as IL-1b,
immediately release a variety of cytokines and chemokines, IL-6, TNF-a, etc. to initiate immune defense. Therefore, astrocytes
directly and non-specifically killing tumors and other aberrant and microglia are important players in many neurological
cells as well as aging cells. NK cell-mediated immunotherapy has disorders, regulating neuroinflammatory responses (48–50).
become a focus of research for the treatment of cancer and other Previous studies have shown that acupuncture can achieve anti-
immunosuppressive diseases due to its potent cytotoxic effects on inflammatory and neuroprotective effects by modulating the
aberrant cells in the body (37, 38). NK cells are generally quiescent inflammation of the nervous system caused by neurological disorders
under normal physiological settings, but when activated, they can such as Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic
infiltrate tissues and release cytotoxic granules containing perforin brain injury (TBI), spinal cord injury (SCI), etc., alleviating the
and granzyme, which directly lyse aberrant cells and have a killing pathological reaction of the disease. In cerebral ischemia-reperfusion
effect (39). IFN, tumor necrosis factor (TNF), and other chemokines disease, inflammatory responses are activated, microglia are activated,
and cytokines that control the adaptive immune response can be and large numbers of circulating inflammatory cells infiltrate the
secreted by NK cells at the same time. damaged areas, leading to the secretion of inflammatory-associated
Prior studies have shown that acupuncture therapy can factors and a cascade of responses that ultimately lead to secondary
significantly boost NK cell activity, regulate the proportion of NK brain damage (51). EA at LI11 (Quchi, Large intestine 11) and ST36
cell subsets, and trigger the release of related cytokines, resulting in acupoints of MCAO rats for 3 consecutive days effectively reduced the
analgesia, regulation of the stress response, relief from symptoms of infarct volume and neurological deficit and improved the velocity,
morphine withdrawal and immunosuppressive effects brought on balance, and coordination of motor function, and the number of BrdU/
by cyclophosphamide, etc (40–43). According to Yu et al., EA NEUN double-positive cells and striatum double-positive cells in the
stimulation of the bilateral ST36 acupoints dramatically elevated brain of EA rats was significantly increased, suggesting that EA may
the toxicity of NK cells in the rat spleen (44). Other research achieve the neuroprotective effect by inducing cells to proliferate and
revealed that EA stimulation of the ST36 acupoint significantly differentiate into astrocyte and mature neurons (52). Another study
increased the levels of IL-2 and IFN-g in the spleen. Cytokine levels found that EA of PC6 (Neiguan, Pericardium 6) and LI11 ameliorated
were also significantly positively correlated with the toxicity of nerve injury and reduce inflammation, which may be related to the
splenic NK cells, with endogenous IFN-g playing a significant role inhibition of the activity of the toll-like receptor (TLR)4-nuclear factor
in the EA’s intervention in the activation of NK Cells (43). kappa-B (NF-kB) signaling pathway in microglia (53). According to
So, how does acupuncture affect the quantity and activity of NK Liu et al., EA ameliorated the degeneration and necrosis of the ischemic
cells in the spleen? According to Ham et al., destroying the lateral penumbra cortical microglia, inhibited the transformation of the
hypothalamus can decrease the activity of NK cells, and microglia to the M1 proinflammatory phenotype, and downregulated
electroacupuncture ST36 can reverse this effect, revealing that the the expression of Iba-1 and CD11b. In addition, it also inhibited the
lateral hypothalamic area (LHA) plays an important role in the expression of NF-kB, IL-1b, and TNF-a (54).
neuroimmunomodulation of NK cells by acupuncture. The use of a For neurodegeneration conditions such as PD or AD, the
lateral hypothalamic injury rat model by Choi et al. also provides activation of microglia and astrocytes is an important
evidence to support these finding (45, 46). When b-endorphin pathological feature (55). In addition, the inflammatory
travels via the circulation to lymphoid tissues like the spleen, it environment can enhance the aggregation of pathogenic a-
binds to opioid receptors found on the surface of NK cells and synuclein, further activate the aggregation and proliferation of
facilitates the activation of NK cells by controlling the production microglia, induce pathological cascade reaction, and aggravate the
and distribution of IFN-g (44, 47). However, it is significant to note disease progression. Therefore, the regulation of microglia and
that LHA damage does not entirely reverse the effects of EA, astrocytes has important clinical significance in disease control (56).
indicating that the regulation mechanism of EA stimulation on Acupuncture can enhance the structure and performance of
NK cells may be more intricate than previously assumed and synapses, activate astroglia and microglia, foster Neuroplasticity,
additional research is required (46). and ameliorate the symptoms of neurological deficits (57). In a

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mouse model of PD, acupuncture treatment reduced the activation regulation of cytokines secreted by CD4+ T cells are the key
of microglia and astrocyte, and inhibited the neuroinflammatory detrimental changes within the pathological progression (67). Th2
response associated with the PD phenotype (58). The activation of and Th17 cells and their cytokines promote the exacerbation of
glial cells in hippocampal CA1 and DG regions and the polarization asthma symptoms, while the regulation of Th1 and Treg cells can
regulation of M2 microglia were observed in AD rats treated with suppress the pathological symptoms of asthma. Therefore, the
EA, and increased levels of anti-inflammatory cytokines (IL-4 and regulation of Th1/Th2 and Th17/Treg balance can alleviate the
IL-10) and decreased levels of Proinflammatory cytokine (TNF-a, symptoms of asthma and provide a therapeutic effect. To date, there
IL-1b, and IL-6) may be associated with NF-kB and STAT6 exist several animal experiments and clinical studies to verify the
pathways (59). effect of acupuncture treatment on asthma, mainly by regulating the
According to extant studies, the mechanism of EA inhibition of number and activity of CD4+ T cells to play an anti-inflammatory
glial cell activation is associated with sensory neurotransmission in role (68). Zhao et al. found that after using ovalbumin to induce
the dorsal root ganglia (DRG). EA has been demonstrated to reduce mouse asthma models and acupuncture at GV14 (Dazhui,
neuropathic pain by inhibiting Toll-like receptor 4 (TLR4) signaling Governing vessel 14), BL13 (Feishu, Urinary bladder 13), and
in DRG neurons, while concurrently upregulating transient ST36 acupoints, the levels of IFN-g in blood and bronchoalveolar
receptor potential vanilloid 1 (TRPV1) to attenuate spinal glial lavage fluid(BALF) were increased and the levels of IL-4, IL-17, and
activation (60). TGF-b were decreased in the treatment group as compared with the
control group, on CD4+ T cells, acupuncture corrected the
imbalance of Th1/Th2 and Treg/Th17 cells (69). Consistent with
3 Acupuncture-induced modulation of this conclusion, Dong et al. observed that after acupuncture
the adaptive immune response treatment of ovalbumin-induced asthma in mice, the activities of
Th1 and Treg cells were enhanced (70).
3.1 Th1/Thbalance and Th17/Treg balance In addition to asthma, acupuncture can be effective in treating
IBS and other diseases by regulating the differentiation of CD4+ T
As one of the most significant subsets of peripheral cells. In a collagen-induced rat model of arthritis, EA can reestablish
lymphocytes, CD4+ T helper (Th) cells affect both innate and the balance of Th17/Treg cells and relieve inflammation of arthritis
adaptive immune responses by producing cytokines and (71). In the ulcerative colitis (UC) mice model group, the expression
interacting with other cells (61). Subsets of CD4+ T cells include of TLR2 and TLR4 in the splenic lymphocytes was up-regulated,
Th1 cells, Th2 cells, Th9 cells, T follicular helper cells (Tfh cells), and the symptoms of UC were significantly alleviated after EA
Th17 cells, Treg cells, and so on. Th1 cells mediate cellular stimulation of ST36 (72). The immunosuppression after surgical
immunity or delayed hypersensitivity (DTH) and promote the trauma can also be effectively relieved by EA. The balance between
inflammatory reaction. They mainly secrete IL-2, IL-6, IL-12, Th1 and Th2 cytokines in the spleen was detected after
IFN-g and TNF-a. Th2 cells mediate humoral immunity, inhibit acupuncture, suggesting the pathway of EA relieving
the inflammatory reaction, and mainly secrete IL-4, IL-5, and IL-10 immunosuppression (73).
(62). In a normal physiological state, Th1/Th2 maintain a certain
balance and jointly maintain the balance of immune function. The
imbalance of Th1/Th2 cells may be the main cause or pathological 3.2 CD8+ T cells differentiation
outcome of some infectious or allergic diseases (63).
In addition to Th1 and Th2, Th17 cells are a third crucial subset CD8+ T cells are a subset of cytotoxic T cells that are essential
of CD4 + T helper cells. By producing IL-17 and other for both tumor and viral defense (74). It can differentiate into
Proinflammatory cytokines like TNF-a, IL-6, IL-22, and IL-21, effector and memory T cells that function to help mediate pathogen
then induced neutrophils migrate to the site of infection in the body, clearance and provide long-term protective immunity (75). In
causing an inflammatory response that is crucial for the emergence antiviral infection, which is mainly mediated by CD8+ T cells,
of autoimmunity (64). Regulatory T (Treg) cells are FOXP3- other immune cells and cytokines have contributed to it. In the
expressing immune cells that are naturally present in the immune presence of persistent antigens created by ongoing infection, CD4+
system. It suppresses the immune response of effector cells by T cells can prevent CD8+ T cells from developing tolerance, and
secreting TGF-b1 and/or IL-10, thereby inhibiting the they can also encourage the recruitment, proliferation, survival, and
proliferation of T helper cells and the production of inflammatory exerting actions of CD8+ T cells in a pathogenic environment (72).
factors, regulating the homeostasis of the body and preventing Acupuncture maintains the homeostasis of the body by
autoimmune diseases (65). There is a crucial plasticity between regulating the differentiation of T cells and the ratio of different
Th17/Treg cells, which maintains the immune balance of the body. lymphocyte subsets. According to Yamaguchi et al., the number of
In inflammatory and autoimmune diseases, the Th17/Treg balance CD2, CD4, CD8, CD11b, CD16, and CD56 cells and the levels of IL-
is broken, which promotes the initiation and maintenance of 4, IL-1b, and IFN-gin human peripheral serum cells increased
inflammation (66). significantly after acupuncture (42). Another clinical study
Asthma is a severe chronic respiratory disease characterized by showed that after acupuncture, the serum total IgE level in
airway hyper-responsiveness, airway inflammation, and airway patients with allergic asthma decreased significantly, showing a
remodeling. The immune response of CD4+ T cells and the good therapeutic effect. At the same time, CD3+, CD4+, and CD8+ T

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lymphocytes in peripheral blood were dramatically increased, inflammation, analgesic anesthesia,and more (84). However, recent
indicating that acupuncture may be mediated by CD8+ T cells studies have demonstrated that acupuncture’s autonomic regulation is
(68). In a mouse model of collagen-induced arthritis (CIA), not as straightforward as that of the sympathetic or parasympathetic
however, the CD4+/CD8+ ratio was maintained in a near-normal pathways. The functions of the sympathetic nervous system and
range in acupuncture compared with the control group, with parasympathetic nervous system are not mutually exclusive, and in
effective suppression of inflammatory responses (54). For sepsis many cases, they collaborate to combat disease (85). Here we provide a
mice, EA could increase the number of CD3+ T cells, maintain the brief review of several acupuncture-regulated neuro-reflex pathways
ratio of CD4+/CD8+ T cells and protect the intestinal mucosal that have been discovered in recent years, such as the vagal-adrenal
immune barrier (76). pathway, the cholinergic anti-inflammatory pathway (CAIP), the
spinal sympathetic pathway, and the involvement of the brain-gut
axis (BGA).
4 Somatosensory-autonomic reflex to
modulate the immune response
4.2 The vagal-adrenal anti-
4.1 Neuroanatomical basis of inflammatory pathway
somatosensory mechanisms for
acupuncture-induced immunomodulation The recently discovered vagal-adrenal pathway is a signal pathway
through which EA stimulation of ST36 acupoint can exert an anti-
Many of the acupoints used in acupuncture have neuroanatomy inflammatory effect. Torres-Rosas et al. found that EA stimulation of
implications consistent with Western medical concepts, and ST36 could effectively inhibit systemic inflammation and improve
acupuncture works on the body through several mechanisms, survival in LPS- and cecal ligation and puncture (CLP)-induced
even though its therapy is based on a completely different set of septic mice. Vagotomy and adrenalectomy could block the anti-
systems from Western medicine. With the development of new inflammatory effect of EA, they, therefore, speculate that EA may act
technologies such as molecular and cell biology, our understanding through the vagal-adrenal pathway. After EA, the levels of
of this practice is deepening. Today, researchers can use various catecholamines, especially dopamine, mainly released from the
research methods to develop and enhance this medical practice, adrenal medulla were dramatically increased. But only after
thanks to some ground-breaking studies in recent years that have dopamine was blocked by an inhibitor, the anti-inflammatory effect
established a research paradigm to explain its neuroanatomy of EA was blocked. And the use of dopaminergic agonists can mimic
mechanism. Acupuncture acts as a non-nociceptive mechanical the effects of EA and control inflammation in mice with adrenal
stimulus, activating a variety of mechanosensitive sensory insufficiency sepsis (86). This demonstrates the existence and
neurons on the skin’s surface. The molecular signals of the stabilization of the vagal-adrenal signaling pathway.
mechanical stimulus are then transduced through primary Further, Liu et al. used genetic manipulation strategy
sensory afferent nerve fibers, projecting to the interneurons of the demonstrating that NPYDBH+ chromaffin cells are involved in this
spinal cord, brainstem, and hypothalamus. These signals are then anti-inflammatory axis (7). It was then shown that low-intensity EA
sent to the corresponding neural pathways via efferent nerves, stimulation (0.5 mA) with PROKR2-Cre + sensory neurons
regulating the body’s feeling, movement, and more (77, 78). dependent can evoke this vagal–adrenal axis from the hindlimb
There are several types of afferent fiber, thick myelinated Aa and ST36 acupoint, but not from the abdominal ST25 acupoint. Even
Ab (group I and II), thin myelinated Ad (group III), and thinner high-intensity EA stimulation (3 mA) of ST25 failed to activate
unmyelinated C (group IV) fibers (79). These fibers, which are mostly vagal parasympathetic efferent neurons located in DMV,
located in the trigeminal ganglion (TG) and dorsal root ganglia demonstrating the acupoint selectivity in driving vagal reflexes.
(DRG), contain peripheral axon branching at the terminals of Activation of this vagal–adrenal axis sufficiently attenuates LPS-
nociceptive receptors that gather and convey impulses to the and CLP-induced systemic inflammation and protects against
surface of the body. The physical basis for the specificity, intensity septic death in mice, and notably, this reflex operates in a disease
and frequency dependence of acupuncture points may be the many state-independent manner, producing anti-inflammatory effects
types of activated peripheral afferent nerve fibers (77). The frequency irrespective of EA stimulation conducted before or after cytokine
of EA stimulation, the position, and the strength of the acupuncture storm has reached peak levels. Thus, EA stimulation can drive this
will all have a varied impact (80–82). Xin et al. found that the pathway and modulate systemic inflammation in a manner
segmental analgesia of EA at ST36 with lower intensity is partially dependent on acupoint selection, and stimulation intensity.
mediated by ASIC3 receptor on Ab-fiber, whereas systemic analgesia
induced by EA with higher intensity is more likely induced by TRPV1
receptor on Ad- and C-fibers (83). This is of great significance to the 4.3 The cholinergic anti-
clinical application of acupuncture treatment. inflammatory pathway
The autonomous nervous system (ANS) is essential in maintaining
the stability of the organism. It is composed mainly of the sympathetic As a neuro-immunomodulatory mechanism regulated by the
and parasympathetic nerves and plays a significant role in vagus nerve, CAIP is responsible for controlling the body’s
acupuncture’s therapeutic effects on gastrointestinal motility, inflammatory response and has a pronounced inhibiting effect on

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both local and systemic inflammation (87–89). Acetylcholine (Ach) sympathetic pathway. Meanwhile, Liu et al. and other studies have
is the primary neurotransmitter of the parasympathetic nervous shown that EA at ST25 can also activate the spinal-sympathetic
system, and it can be received by muscarinic and nicotine receptors pathway and have an anti-inflammatory effect (104). Axons from
expressed by immune cells (90). In CAIP, the nicotinic sympathetic ganglion neurons of the spinal cord enter the adrenal
acetylcholine receptor type 7 subunit (a7-nAChR) binds the gland and terminate in the cells of the adrenal medulla globular
majority of the Ach released from the vagus nerve, which zone, releasing catecholamine and neuropeptide Y (NPY),
prevents NF-kB nuclear translocating and prevents monocyte and suggesting a direct sympathetic nervous system of the adrenal
macrophage cytokine releasing. Regulation of immune responses medulla. After stimulation of the spinal sympathetic pathway,
(91, 92) may be useful in treating or reducing immune sympathetic nervous system control promotes the synthesis and
disequilibrium disorders like inflammatory bowel disease and secretion of noradrenaline in the adrenal medulla, which further
osteoarthritis (93, 94). activates the b2-adrenergic receptor of splenic cells and regulates
Vagus nerve stimulation has emerged as a promising the activation of inflammatory cells, the secretion of pro-
therapeutic approach in recent years, activating anti-inflammatory inflammatory and anti-inflammatory factors, produces anti-
pathways through cervical and trans-auricular electrical inflammatory effects.
stimulations (95–97). However, this treatment requires invasive The spinal sympathetic pathway can be activated by
surgery, with some associated risk (98). Acupuncture at specific acupuncture at multiple acupoints. In LPS-induced septic mice,
acupoints also can effectively activate the vagus nerve and achieve EA at ST25 of 3 mA significantly decreased proinflammatory
anti-inflammatory effects through CAIP (99, 100). By contrast, its cytokine IL-6 and IL-1b, and up-regulated the anti-inflammatory
non-invasive nature and low risk make it an ideal alternative to cytokine IL-10, increasing the survival rate of septic mice. Another
inflammatory therapy. study used 1 Hz low-frequency EA to stimulate the ST36 acupoint
Song et al. found that CAIP activation played an important role in and found that sympathetic ganglion neurons were activated and
the process of EA stimulation of ST36 to inhibit the inflammatory acted on the b-adrenergic receptor of immune cells to suppress the
response in septic rats. Suppressed inflammatory responses are yeast polysaccharide-induced peripheral inflammatory response
exacerbated after the bilateral vagal blockade, and similarly, ST36 EA (105). EA with Li4 can significantly inhibit systemic inflammation
no longer has an anti-inflammatory effect after the use of the a7-nAchR and improve the survival rate in LPS-induced lethal sepsis rats. This
antagonist a-BGT (101). Consistent with the results of this study, EA specific anti-inflammatory effect requires activation of the
stimulation of Li4 (Hegu) can also significantly inhibit the inflammatory sympathetic nervous system (100). After sympathectomy, the
reaction in endotoxemia rats and improve the survival rate. The spleen anti-inflammatory effect was significantly suppressed when 6-
is an important organ in this anti-inflammatory pathway. The vagus hydroxy dopamine (6-OHDA) was used, indicating that the
nerve terminates in a synaptic-like structure around the main cells of the sympathetic nerve is involved in mediating the anti-
celiac-superior mesenteric plexus, where the catecholaminergic splenic inflammatory effects.
fibers originate. EA at Li4 can activate the vagus nerve and increase the
noradrenaline released by the spleen. The adrenergic receptor, which is
expressed in B and T cells of the spleen, produces acetylcholine, and 4.5 The brain-gut pathway
anti-inflammatory effects are achieved by activating the nicotinic
acetylcholine receptor expressed on macrophages and inhibiting the The bidirectional communication and coordination between
release of related pro-inflammatory factors (100). the brain and the intestine are mainly mediated by the brain-gut
Besides systemic inflammation, acupuncture at specific acupoints axis (BGA) (106). The role of the BGA in the maintenance of
can also exert its effect on local inflammation through CAIP. In the homeostasis has been extensively studied over the past decade. It is
chronic obstructive pulmonary disease (COPD) rat model, acupuncture crucial for preserving homeostasis in the organism, particularly that
at ST36 and BL13 can down-regulate the levels of inflammatory of the immune system (107). The brain-gut signaling pathway
cytokines, reduce the inflammatory reaction of lung tissue and mainly involved the central nervous system (CNS), the enteric
improve lung function. Furthermore, the enhancement of the cervical nervous system (ENS), the autonomic nervous system (ANS), the
vagus nerve discharge signal was observed in the experiment, and the hypothalamus-pituitary-adrenal (HPA) axis, and others. These
effect of EA was blocked after antagonizing the action of a7-nAChR pathways regulate the gut microbiota, brain-gut peptides, local
with a-BGT (102). EA stimulation of ST36 could inhibit the immune systems in the gut, and so on. Through the BGA, signals
inflammatory reaction and then reduce the infiltration of white blood from the brain affect the body’s sensory, motor, and gut microbiota.
cells in the mice model of acute pancreatitis. This regulatory effect can be In contrast, gut microbiota and peptides can further influence brain
blocked by vagotomy and a-BGT, suggesting an important role of CAIP function (108). This pathway plays an important role in the
in this process (103). pathology of neurodevelopmental disorders, neurodegeneration,
gastrointestinal disorders, and others, which is widely considered
a novel therapeutic target for disease (108–111).
4.4 The spinal-sympathetic pathway IBS is a widely recognized functional gastrointestinal disorder,
which is often seen as a pathological consequence of BGA disease
As described above, high-intensity EA stimulation of ST25 does (111). In addition to typical symptoms such as abdominal pain,
not activate the vagal-adrenal axis but rather drives the spinal cord abdominal distention, intestinal dysfunction, low-grade

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Wang et al. 10.3389/fimmu.2023.1147718

inflammation, and local immune activation, something else has hyperresponsiveness, reduce lymphocyte count in BALF,
been observed in the intestinal wall of patients, which may lead to attenuate airway inflammation and secretion of associated
neurological dysfunction and impaired immune system within the inflammatory cytokines, increase levels of corticotropin and
intestinal mucosa (112). Acupuncture has been used to treat cortisol in plasma, suggesting that the activity of the HPA axis
gastrointestinal disorders for millennia, and its regulatory role in may be implicated in the immune regulation of airway
IBS and other gastrointestinal disorders has been confirmed by inflammation (123). Acupuncture can regulate the homeostasis of
several clinical and basic studies (113, 114). Sun et al. found that the body by regulating the HPA axis, inhibiting and alleviating the
acupuncture at acupoints ST36 and ST25 in IBS mice alleviated IBS- inflammatory response that may be induced by stress (124).
like symptoms and significantly reduced the content of 5-
hydroxytryptamine (5-HT) and CGRP in BGA, increasing the
content of NPY (115). Another study showed that EA could 6 Perspectives and conclusions
decrease the expression of CRF and CRF-R1 in the hypothalamus
of IBS rats, relieve anxiety and depression, decrease the expression Currently, some human experiments suggest that there is no
of CRF-R1 in the gastrointestinal mucosa, and increase the significant difference in therapeutic effect between the acupuncture
expression of ZO-1. Regulation of the tight junction, which group and the sham-acupuncture group (which was designed by
repairs the intestinal mucosal barrier, suggested a potential dual attaching a blunt to the epidermis instead of inserting the skin),
therapeutic role for EA in the regulation of disturbed gut-brain leading to the conclusion that the acupuncture effect is negated.
interactions in IBS rats (116). However, it is important to note that the sham needle group did not
In another study conducted by song et al. in the post- undergo complete control in the experimental design. There are a large
inflammatory irritable bowel syndrome (PI-IBS) model using number of c-low threshold mechanical receptors and nonpeptidergic
trinitrobenzene sulfonic acid (TNBS) induction, electroacupuncture sensory nerve fibers innervate the epidermis, and these receptors
stimulation of ST25 and ST36 acupoints could have a positive effect somehow be activated by blunt needle and then cause a response.
on alleviating visceral allergy symptoms and protecting the intestinal Additionally, there have been numerous animal experimental studies to
mucosa by changing the number and type of microflora in the explore the physiological mechanism of acupuncture, which provides a
intestine (117). solid theoretical basis for acupuncture therapy. Therefore, the results of
In this process, acupuncture, a non-invasive nerve stimulus, the current human experimental design are not sufficient to
may control intestinal inflammation and the secretion of related conclusively disprove the efficacy of acupuncture treatment.
neurotransmitters through a somatosensory-autonomic reflex In this review, we incorporated and covered the
pathway, thereby restoring the balance of BGA (118). Alterations immunomodulatory function and mechanism of acupuncture
in the gut microbiota and signals of immune activation can be practice. In addition to dramatically regulating immune cells and
transmitted to the brain via the vagus or sympathetic nerves, thus molecules, including innate and adaptive immune responses,
establishing a bidirectional brain-gut regulation (119). However, acupuncture can stimulate and support immunological responses
further exploration of the specific regulatory pathway is needed. that are anti-inflammatory and anti-infectious. It then discusses how
acupuncture controls the immune response. A particular conduction
pathway is used by the mechanical stimulation signal of acupuncture to
5 HPA axis involved with affect immunological organs and cells (See Figure 1). It is essential to
immunoregulation by acupuncture promote the use of acupuncture as a scientific medical practice, to some
extent, led to a breakthrough in our understanding of the effects and
The hypothalamus-pituitary-adrenal axis (HPA axis) appears to characteristics of acupuncture therapy. Despite the numerous advances
be one of the most significant stress reactions and is crucial for in the field of acupuncture, there remain many challenges. The
energizing and re-establishing the body’s equilibrium. The HPA regulatory effect of acupuncture on the body often acts on multiple
axis is triggered by multiple stimuli, including physiological, systems simultaneously, such as the regulation of the neural-endocrine-
psychological, and immunological, which promote the synthesis immune network. This is in line with the holistic perspective of TCM,
and release of glucocorticoid and other hormones throughout the which suggests that the therapeutic effect of acupuncture practice is
body (120). According to relevant studies, the autonomic nervous frequently the result of the integration of a multi-system network. It is
system plays a role in the regulation of the HPA axis (121). The now challenging to properly comprehend the regulatory impact of the
involvement of the HPA axis in the regulation of immune diseases system on the organism because the majority of related mechanism
by acupuncture indicates the fine regulation of the nerve-endocrine- research is concentrated on a single system and the outcomes are too
immune network by acupuncture. dispersed. Consequently, further research is needed to ascertain how
Zhang et al. found that in a mouse model of CFA-induced acupuncture affects the body’s immune system as a whole.
inflammation, EA at 10 Hz suppressed peripheral inflammation by Medical research in western countries has largely relied on
activating the HPA axis and the nervous system, whereas reductionist approaches, which seek to understand the individual
adrenalectomy was performed to block the HPA axis (10), there components of a complex system at the molecular level. While this
was no significant decrease in inflammation levels relative to the approach has been successful in managing associated symptoms, it
control group (122). For an OVA-induced asthma mouse model, has not been as successful in treating complex diseases, such as
acupuncture was demonstrated to effectively inhibited airway sepsis, severe arthritis, gastrointestinal disorders and neurological

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Wang et al. 10.3389/fimmu.2023.1147718

FIGURE 1
Acupuncture evoked pathways for modulating innate and adaptive immune responses. After acupuncture evoked a mechanical and thermal stimulus
within acupoints, the generated electrical signal then transmitted by somatic sensory fibers to the central nervous system, and produced distinct
descending regulatory pathways. Such as the cholinergic anti-inflammatory pathway, the vagal-adrenal pathway, the spinal-sympathetic pathway,
and the brain-gut pathway. These pathways then to restoring the immune homeostasis by moderating innate (A) and adaptive (B) immune
responses. (A) Acupuncture modulates the innate immune response by regulating innate immune cells’ activity and the capacity of release cytokines.
The proliferation and differentiation of pro-inflammatory M1 macrophages can be blocked by acupuncture, whereas the number of anti-
inflammatory M2 phenotypes is increased, along with the secretion of anti-inflammatory cytokines such as IL-10 and TNF-b. Acupuncture can
regulate the quantity and activity of neutrophils and reverse the migration of neutrophils to the site of inflammation. NK cells can release cytotoxic
granules containing perforin and granzyme to Lyse and kill abnormal cells, and acupuncture can increase the number and activity of NK cells. In the
central nervous system, astrocytes and microglia can be modulated by acupuncture to reverse the activated state, and reduce the inflammatory
responses. (B) Acupuncture primarily controls the adaptive immune system by controlling the development of T cells, which produces CD4+ T cells
for humoral immunity and CD8+ T cells for antiviral immunity. The balance between pro-inflammatory Tregs and anti-inflammatory Th17, as well as
between pro-inflammatory Th1 and anti-inflammatory Th2, is regulated by acupuncture. Maintaining the ratio of CD4+/CD8+ T cells while
controlling the quantity and activity of CD8+ T cells will help the body’s immune homeostasis.

disorders. Because complex diseases involve many redundant Funding

molecular and cellular pathways, making it difficult to target
them all. The development of system physiology offers potential This work was supported by the National Key R&D Program of
solutions to this problem. System physiological research focuses on China (No. 2022YFC3500700), the National Natural Science
elucidating the interplay between various systems in the disease Foundation of China (No. 82274228), the Lingang Laboratory
process, such as the dynamic interaction between neuro-immune- (No. LG-QS-202203-12), and the Undergraduate Research
target tissues. This approach echoes the holistic view of ancient Program sponsored by MOE Frontiers Center for Brain Science.
acupuncture practices, which emphasize the mobilization of self-
healing mechanisms to restore body homeostasis, rather than just
treating the symptoms. With the advances made in recent systems Conflict of interest
physiology studies, we now have a great opportunity to gain insight
into how acupuncture works to modulate immunity, and The authors declare that the research was conducted in the
subsequently improve its efficacy. absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.

Author contributions
Publisher’s note
MW wrote the original draft. WL, JG and SL edited the
manuscript. All authors contributed to the article and approved All claims expressed in this article are solely those of the authors
the submitted version. and do not necessarily represent those of their affiliated

Frontiers in Immunology 09 frontiersin.org

Wang et al. 10.3389/fimmu.2023.1147718

organizations, or those of the publisher, the editors and the claim that may be made by its manufacturer, is not guaranteed or
reviewers. Any product that may be evaluated in this article, or endorsed by the publisher.

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