Mechanisms,of,immune,regulation,for,acupuncture,on,chronic,respiratory,diseases

WEI Meng,LI Yu,XIONG Chan,LIU Yefang,LIANG Fanrong,MAO Bing,MIAO Tiwei,HUANG Ying,ZHU Yijing,FU Juanjuan

WEI Meng,HUANG Ying,ZHU Yijing,Chengdu University of Traditional Chinese Medicine,No.3 Affiliated Hospital of Chengdu University of Traditional Chinese Medicine (West District)/Chengdu Pidu District Hospital of Traditional Chinese Medicine,Chengdu 611730,China

LI Yu,XIONG Chan,LIU Yefang,Respiratory Department,No.3 Affiliated Hospital of Chengdu University of Traditional Chinese Medicine (West District)/ Chengdu Pidu District Hospital of Traditional Chinese Medicine,Chengdu 611730,China

MAO Bing,MIAO Tiwei,FU Juanjuan,Department of Integrated Traditional and Western Medicine,West China Hospital,Sichuan University,Chengdu 610041,China

LIANG Fanrong,Acupuncture and Tuina School,Chengdu University of Traditional Chinese Medicine,Chengdu 610053,China

Abstract Chronic respiratory diseases (CRDs) are among the most common noncommunicable diseases globally,with high morbidity and mortality rates.Acupuncture,a treatment method derived from Traditional Chinese Medicine,has been shown to be effective at treating CRDs,with little risk of adverse effects.Scientific research on the mechanisms underlying the effects of acupuncture,especially,its immune regulatory function,has rapidly advanced in recent years.Herein,the diverse immune regulatory mechanisms underlying the beneficial effects of acupuncture are summarized from the perspectives of innate immunity,adaptive immunity,and neuroimmunity.A better understanding of these mechanisms will ultimately provide a scientific basis for the clinical use of acupuncture for the treatment of CRDs.

Keywords:acupuncture;immunity,innate;adaptive immunity;neuroimmunomodulation;chronic respiratory diseases

Chronic respiratory diseases (CRDs) are defined as chronic diseases of the respiratory tract and other structures of the lungs,with chronic obstructive pulmonary disease (COPD),asthma,interstitial lung disease,occupational lung disease,pulmonary hypertension,and lung cancer being the most common types of CRDs.1In recent years,the number of patients with CRDs has increased sharply,and 544.9 million people worldwide were diagnosed with CRDs in 2017.2According to the rankings of the top ten causes of death in the 2019 global health statistics report released by the World Health Organization,COPD and lung cancer rank third and sixth,respectively.3

Current treatment schemes for CRDs have limitations.Inhalation therapies,including long-acting beta2-adrenergic agonists,long-acting muscarinic antagonists,and corticosteroids,are the first-line treatment options for COPD and asthma,which relieve patient symptoms by relaxing airway smooth muscle and/or alleviating airway inflammation to a certain extent.4However,prolonged use of these medications can cause adverse effects,such as oropharyngeal candidiasis,cough,hoarseness,cataract,diabetes,and osteoporosis.5,6Acupuncture is one of the most important treatment methods in the Traditional Chinese Medicine system and has been practiced in China for more than 3000 years.Acupuncture has also been applied in patients with CRDs and is advantageous for improving respiratory symptoms,lung function,exercise tolerance,and quality of life,with little risk of serious adverse effects.7However,the physiological and biological mechanisms underlying the beneficial effects of acupuncture against CRDs are still poorly understood.By searching PubMed,Web of Science,Excerpta Medica Database,China National Knowledge Infrastructure (CNKI),Wanfang,and other relevant databases,we reviewed and summarized the mechanisms underlying acupuncture-mediated immune regulation in CRDs from the perspective of innate immunity,adaptive immunity,and neuroimmunity.A better understanding of these mechanisms will provide a scientific basis for the further clinical utilization of acupuncture in the treatment of CRDs.

Innate immunity,also known as nonspecific immunity,is a natural defense mechanism that is gradually formed in the process of long-term ethnic development and evolution,but can also be obtained without antigen stimulation.Innate immunity can not only resist invasion by pathogenic microorganisms or harmful substances,but also eliminate pathogens by dissolution and phagocytosis.In addition,innate immunity plays a key role in the initiation,effects,and regulation of adaptive immunity (Figure 1 in Supplementary Appendix).

Pattern recognition receptors (PRRs) are proteins mainly expressed on the surface of innate immune cells;they recognize pathogen-related molecular patterns.PRRs readily monitor invasion by bacteria or virus particles and initiate inflammatory responses and antibacterial or antiviral immunity to prevent infection of the host.Tolllike receptor 4 (TLR4) is one of the main PRRs that play a role in conditions associated with chronic airway inflammation,such as COPD.TLR4 recognizes lipopolysaccharides produced by gram-negative bacteria and activates downstream nuclear factor-kappa B (NFκB) and mitogen-activated protein kinase (MAPK)pathways in a “waterfall” cascade through myeloid differentiation protein 88 (MyD88)-dependent and MyD88-independent pathways.Activation of the NF-κB and MAPK pathways promotes the release of inflammatory factors,such as interleukin (IL)-1β,IL-6,and tumor necrosis factor (TNF)-α from alveolar macrophages,enhancing airway inflammation.8,9Studies have shown that electroacupuncture stimulation of acupoint Feishu (BL13),Shenshu (BL23),and Dazhui(GV14) can regulate the TLR4/NF-κB pathway in both human and animal models of COPD by inhibiting the expression of the TLR4 and NF-κB proteins and reducing the release of inflammatory cytokines (IL-1β and IL-6) from alveolar macrophages.10The receptor for advanced glycation end products (RAGE) is another important PRR that exists in the body in two main forms:membrane-bound RAGE (mRAGE) and soluble RAGE(sRAGE).mRAGE combines ligand advanced glycation end products (AGEs) to promote cellular oxidative stress,NF-κB activation,and signal cascade reactions.mRAGE is found to play a role in aggravating the damage of the vascular epithelium in the respiratory tract of patients with COPD.11However,sRAGE competitively binds to AGEs,thereby reducing the damage caused by inflammatory responses in CRDs.12Acupuncture at Dazhui (GV14),Fengmen (BL12),and Feishu (BL13)has been shown to significantly reduce the number of eosinophils in the bronchoalveolar lavage fluid (BALF)of ovalbumin-induced asthmatic rats.The mechanism is related to the downregulation of the pro-inflammatory protein,mRAGE,and upregulation of the antiinflammatory protein,sRAGE,collectively resulting in the inactivation of the NF-κB or MAPK signaling pathways.13

Pulmonary surfactant (PS) is a lipoprotein complex synthesized and secreted by alveolar type Ⅱ epithelial cells and bronchial epithelial Clara cells that can reduce alveolar surface tension and maintain alveolar stability.Macromolecular hydrophilic surfactant protein (SP)-A,a type of PS,plays an important role in the fight against viral and bacterial infections in the innate lung defense system.The innate defense mechanism of SP-A involves the binding of thyroid transcription factor-1 and NF-κB protein,the enhancement of the activity of tubular myelin structure,and the maintenance of alveolar stability and lung tissue compliance.14Previous studies showed that acupuncture at “three needles and five points,” that is,Dazhui (GV14),bilateral Feishu (BL13),and bilateral Fengmen (BL12),significantly increased the expression of the SP-A protein and mRNA in the BALF of asthmatic rats;this increase was associated with improved airway resistance,bronchial surface tension,and bronchial smooth muscle spasm.15

Matrix metalloproteinases (MMPs) are a family of extracellular proteinases mainly secreted by macrophages.MMPs play an essential role in the local proteolysis of the extracellular matrix and leukocyte migration.MMP-9 is closely related to the activation of an inflammatory response,destruction of bronchial and alveolar wall integrity,protease-antiprotease imbalance,and oxidative stress.16,17Electroacupuncture can significantly inhibit the abnormal release and activation of MMP-9 in lung tissue of rats with COPD,alleviate diffuse edema and inflammatory cell infiltration,and reverse the pathological changes of COPD.18Another study found that low-frequency electrical stimulation in asthmatic guinea pigs can downregulate the expression of MMP-9 in the BALF and inhibit the proliferation of fibroblasts and vascular endothelial cells in the lung structure,ultimately preventing airway remodeling.19

Adaptive immunity,also referred to as acquired immunity,is induced after stimulation with microbial or antigenic substances.Adaptive immunity involves a tightly regulated interplay between antigen-presenting cells (APCs) and T and B lymphocytes,which facilitates pathogen-specific immunologic effector pathways,generation of immunological memory,and regulation of host immune homeostasis (Figure 2 in Supplementary Appendix).

APCs,including macrophages and dendritic cells (DCs),can absorb,process,and present a variety of antigens,such as those from viruses and bacteria residing in the airways,to T lymphocytes.Studies have found that mature DCs can markedly express costimulatory molecules (such as CD80 and CD86),provide a second activation signal for the full activation of T cells,circumvent T cell disability,and effectively induce immune response.20Further,electroacupuncture at Zusanli (ST36) and Feishu (BL13) can downregulate the MyD88/NF-κB p65 signaling pathway,inhibit the expression of the CD86 molecule in lung tissue,and improve the pulmonary function of COPD rats.21

CD4+T cells can resist invasion by bacteria and microorganisms,enhancing the immune ability of the body,while CD8+T cells release effector molecules(such as perforin and granzyme),promote the apoptosis of their corresponding elastases,destroy the structure of alveolar epithelial cells,and promote the proliferation and hypertrophy of smooth muscle cells.22CD8+T cells can also stimulate inflammatory responses by secreting a large number of inflammatory factors,such as TNF-α and interferon (IFN)-γ.23Studies have shown that acupuncture can reduce the levels of TNF-α,IL-1β,and IL-33 and its receptor,ST2,and alleviate the damage of CD4+T cell subsets in mice with ovalbumin-induced asthma,inhibiting the secretion of mucin by airway epithelial goblet cells and alleviate airway stenosis and ventilation dysfunction.24Zhaoet al25found that acupuncture at Dazhui (GV14),Feishu (BL13) and Zusanli (ST36) can inhibit autophagy-related gene 5-mediated autophagy to regulate endoplasmic reticulum stress and CD4+T lymphocyte differentiation,and reduce asthma airway inflammation and hyperresponsiveness.Based on clinical trials,acupuncture treatment of "Tiaoyi Sanjiao" can alleviate the symptoms of cancer-related fatigue in patients with advanced nonsmall cell lung cancer (NSCLC),significantly increase the level of CD4+T cells and the ratio of CD4+/CD8+T cells,and enhance the immune ability of patients to resist external pathogens and kill tumor cells.26

T helper (Th) 1 and Th2 cells,the main subtypes of Th cells,play important roles in airway inflammatory response.Th1 cells mainly secrete inflammatory cytokines,such as IFN-γ and IL-2,and participate in the mediation of cellular immune response.In contrast,Th2 cells mainly secrete anti-inflammatory cytokines,such as IL-4 and IL-5,which promote the production of antibodies and mediate humoral immune response.27Airway inflammation in COPD is well recognized to be mainly related to Th1 cells,while airway inflammation in asthma is mainly related to the hyperfunction of Th2 cells.28Electroacupuncture stimulation of bilateral Feishu (BL13) and Zusanli (ST36) has been found to inhibit Th1 responses and the release of inflammatory cytokines (such as IFN-γ),prevent the expression of adhesion molecules in endothelial cells,reduce vascular permeability,and alleviate airway remodeling and pulmonary ventilation function in a rat model of COPD.29Other studies have shown that acupuncture at Zusanli (ST36) can upregulate the expression of proapoptotic genes (e.g.,Fas) and downregulate the expression of anti-apoptotic genes (e.g.,B-cell lymphoma-2),reduce eosinophil infiltration in local tissues,block the release of leukotriene B4 and nitric oxide and then inhibit the secretion of Th2 immune cells and the combination of IL-4 and IL-4 receptor α chain,and ultimately,alleviate smooth muscle spasm and airway hyperresponsiveness in asthmatic rats.30,31The proliferation and differentiation of Th1 cells and their secreted pro-inflammatory factors (such as IL-2 and IFNγ) can also promote the immune surveillance of tumor cells.32Acupuncture at the Sihua point can induce the proliferation of Th1 cells and increase the concentration of the inflammatory factor,IFN-γ,and IL-2,maintain Th1/Th2 balance and then inhibit the growth of tumor cells,and avoid the occurrence of tumor escape in patients with advanced NSCLC after chemotherapy.33

Th17 cells are another Th cell type discovered in recent years.Th17 cells can promote the expression of retinoidrelated orphan receptor-gamma-t (RORγt),and then secrete pro-inflammatory factors,such as IL-17 and IL-22,to aggravate allergic airway hyperresponsiveness.34Treg cells are a type of T cell subset that can maintain the immune tolerance of the body.They mainly promote the expression of forkhead box (Fox) p3,inhibit the activation and proliferation of effector T cells,and reduce allergic airway inflammation and delay airway remodeling.35Acupuncture was found to potentially reduce lung inflammation and mucus secretion in asthmatic mice by inhibiting the activation of I kappa B kinase (IκK)-α and p65 protein phosphorylation,and reduce the NF-κB gene expression and the proportion of Th17 cells.36In addition,acupuncture can inhibit the expression of Notch-1 signaling-associated components,reduce the proportion of Th17 cells,increase the proportion of Treg cells,inhibit fibroblast differentiation and smooth muscle proliferation,and alleviate airway inflammation remodeling in asthmatic rats.37,38As a strong inducer of Treg cells,IL-10 is closely related to the production of Treg cells and the occurrence and development of tumor cells.39Acupuncture can inhibit the production of IL-10,prevent the activation of phosphatidylinositol-3-kinases (PI3K)/protein kinase B(Akt),translocate the transcription factor,Foxo1,induced by its phosphorylation to the nucleus,inhibit the expression of downstream Foxp3 and then inhibit the production of Treg,and enhance the immune surveillance effect of the body on tumor cells in patients with NSCLC.40,41

Programmed death-1 (PD-1),a type I transmembrane glycoprotein,is primarily expressed on the surface of immune cells.When combined with programmed death ligand-1 (PD-L1) produced by tumor cells,PD-1 inhibits the activation of PI3K/Akt in its cytoplasmic region and the negative regulation of downstream signals,reduces the original immune killing function,and finally,leads to the immunologic escape of tumor cells.42Acupuncture can inhibit p53 protein mutation,suppress the overexpression of B-cell lymphoma-2 protein,and then,inhibit the expression of PD-L1 and promote the apoptosis of NSCLC cells.43,44When the expression levels of the surface markers of natural killer (NK) cells(such as CD16 and CD56) are reduced,the immune function of the body decreases and tumor cells cannot be effectively killed.45However,acupuncture can increase the activity of NK cells,promote the production of IFNγ from these cells,stimulate the activation of tumorinfiltrating lymphocytes,specifically increase their ability to recognize cancer cells,and suppress the high expression of PD-L1 on the surface of tumor cells,ultimately preventing the immune escape of tumor cells in patients with NSCLC.46,47Acupuncture,as an inhibition method,can effectively prevent signal transduction of the PD-1/PD-L1 pathway and prevent tumor cells from escaping the recognition and attack of the immune system.Thus,acupuncture may act as a complementary therapy for patients with lung cancer.

Immunoglobulin is an important weapon against bacterial and viral infections,involving and bridging both innate and adaptive immunity.Secretory immunoglobulin A (SIgA),one of the main components of mucosal innate immunity,is the first line of defense against pathogens,microorganisms,and other harmful substances that invade the body.Acupuncture was found to relieve cough and wheezing symptoms in children with acute bronchitis by promoting the binding of SIgA with bacteria on the mucosal surface to form the SIgA antigen complex and thus,accelerate the clearance of bacteria from the airways.48Injecting a desensitization solution at Zusanli (ST36) can also significantly increase the level of serum SIgA,improve the airway hyperresponsiveness caused by allergens,enhance the body"s immunologic tolerance,and improve the peak respiratory flow rate in patients with allergic asthma.49The potential mechanism underlying the effects of acupuncture may involve the increase in the concentration of SIgA and the improvement of the defense ability of the respiratory mucosa against viruses or bacteria,to alleviate the clinical symptoms of CRDs.Acupuncture can promote the production of antibodies(IgA,IgM,and IgG) in serum,thereby promoting the neutralization of bacterial toxins,inhibiting the infiltration of inflammatory cells in the lung,and increasing the resistance to bacteria and viruses in patients with chronic asthmatic bronchitis.50Acupuncture can also significantly improve the levels of serum IgA and IgM antibodies,ameliorate metabolic disorders of the body,and improve the immune function of patients with lung cancer.51Acupuncture can also regulate the release of cytokines,such as IL-4,and indirectly reduce the level of IgE and inhibit its binding to IgE-Fc receptor I (FcεRI) on the surface of mast cells and basophils,inhibiting their degranulation,which ultimately reduces vascular permeability,smooth muscle contraction,and gland secretion in patients with asthma.52,53

The immune system is affected and regulated by other systems,among which the regulation of the nervous and endocrine systems is the most important (Figure 3 in Supplementary Appendix).As early as 1977,Besedovskyn proposed the network hypothesis of neuroendocrine immunity and made it clear that a twoway transmission mechanism exists among the nervous,endocrine,and immune systems.54Studies have found that an imbalance in the neuroendocrine immune network can cause vascular endothelial relaxation dysfunction,increase vascular permeability,and activate airway oxidative stress response,which can lead to chronic airway inflammation,such as asthma.55

Neuropeptides are a type of special information substance widely present in human and mammalian somatic nerve tissues.Neuropeptides distributed in the lung tissue can act as neurotransmitters or neuromodulators and affect the function of the airway and pulmonary vessels.56Substance P and vasoactive intestinal polypeptide (VIP) are typical neuropeptides that can affect the inflammatory response of neurogenic airway diseases.57The interaction of SP with its preferred receptor,neurokinin 1 receptor (NK-1R),can lead to the activation of NF-κB and proinflammatory cytokines.58Acupuncture is found to reduce the production of SP and the expression of NK-1R in bronchial epithelial cells,which results in the downregulation of p38 MAPK inflammatory pathway and the alleviation of airway hyperresponsiveness in allergic asthmatic rats.59,60Based on recent studies,acupuncture at Beishu point can inhibit the release of SP,reduce mucus and plasma secretion,relax bronchial smooth muscle,and ultimately,inhibit the occurrence of neurogenic inflammation.61,62VIP released from neuronal and/or nonneuronal exerts immunomodulatory effects by directly binding to VIP receptors (VIP-Rs),which are expressed on most immune cells.63Acupuncture increases the level of VIP and promotes the expression of VIP-R1,preventing further aggravation of asthma.64,65

The vagus nerve mainly participates in homeostatic regulation of visceral function.Recent studies have shown that acupuncture affects vagus nerve excitability and its cholinergic anti-inflammatory pathway.66Acupuncture stimulates vagus nerve excitation,activates the parasympathetic neurotransmitter acetylcholine(Ach),which is released from its peripheral nerve terminals and interacts with α-7-nicotinic Ach receptors(α7nAchRs),inhibits the abnormal activation of signal transduction pathways,such as Janus kinase 2/ signal transducer and activator of transcription 3(JAK2/STAT3),and NF-κB,as well as the synthesis and release of inflammatory factors (such as TNF-α and IL-1β) from macrophages,reduces the inflammatory infiltration of lung tissue,and alleviates inflammatory reactions of the airway in rats with COPD.67Further,acupuncture inhibits the over-excitation of the vagus nerve and maintains the balance of immune function.Studies have confirmed that specific acupuncture of Feishu (BL13) can reduce the lung expression of choline acetyltransferase (ChaT),restore the expression of the muscarinic receptors M1 and M2 (especially in the bronchiolar epithelium),inhibit the overexcitation of the vagus nerve,reduce the proportions of eosinophils,neutrophils,and lymphocytes in BALF,and reduce the local inflammatory response in allergic asthmatic rats.68

As an exogenous nerve stimulation,acupuncture has been widely used as a clinical treatment;however,the mechanism underlying the effects of acupuncture on the autonomic nervous system need to be investigated further.

Acupuncture improves hypothalamic-pituitary-adrenal(HPA) axis activity.As an advanced center regulating visceral and endocrine activities,hypothalamus activation can promote the secretion of a variety of inflammatory mediators (such as histamine) and inflammatory cytokines (such as IL-4,IL-5,IL-13,and TNF),increase airway mucus secretion,and reduce the antioxidant activity in the airway.69,70Studies have found that acupuncture can induce the hypothalamic paraventricular nucleus to secrete corticotropin releasing hormone,change the status of the HPA axis from low reactivity to high reactivity,promote the anterior pituitary to induce adrenocorticotropin,increase the level of endogenous cortisol in ovalbumin-induced asthmatic mice,enhance the antioxidant capacity in the airway,reduce the inflammatory reaction in the airway,and improve the immune function of the body.71Acupuncture treatment can also alleviate the systemic corticosteroid therapy-induced inhibition of the activity of the HPA axis,reduce the dependence of patients with asthma on corticosteroids,and improve the immune homeostasis of the body.72

The clinical effectiveness of acupuncture against CRDs has been demonstrated;however,the mechanisms underlying its effects remain unclear.By reviewing the existing literature,we found that the related mechanisms underlying the immune-regulatory activity of acupuncture in CRDs may involve multiple aspects of immunity,including innate,adaptive,and neuroendocrine immunity.Research on the mechanisms underlying acupuncture-mediated immune-regulation in CRDs is still a relatively new field.Accordingly,future studies are warranted to address the following aspects.Firstly,most current research involved animal experiments.Clinical studies with patient samples will provide direct evidence regarding the mechanisms underlying the beneficial effects of acupuncture in the treatment of human CRDs.Secondly,immune system is a complex network that integrates various types of cells and molecules.Although most studies have focused on a single mechanism,acupuncture may play a therapeutic role through multiple targets and mechanisms.Finally,exploring novel immune mechanisms,such as the modulation of the circadian rhythm of immunity and lung microbiota,by acupuncture may also provide new insights justifying its use in CRDs.Further,an in-depth investigation of the mechanisms underlying the therapeutic effects of acupuncture in CRDs will provide a scientific and theoretical basis for its clinical application and promotion worldwide.

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