A Neuro-Immune Efferent Pathway and the Cholinergic Anti-Inflammatory Axis of Acupuncture

1. From Central Integration to Outgoing Anti-Inflammatory Signals

The central nervous system (CNS) is not only where the body processes signals from disease and inflammation, but also where acupuncture signals are integrated and transformed into outgoing regulatory commands.

When acupuncture is applied, studies show that it can:

• Activate interneurons in the brainstem, especially the nucleus tractus solitarius (NTS)
• Engage several neuro-immune efferent pathways, including: the cholinergic anti-inflammatory pathway (CAIP), the vagus–adrenal medulla–dopamine pathway, sympathetic pathways, and the HPA axis

Together, these pathways provide rapid “first aid” regulation and longer-lasting endocrine–immune modulation, allowing acupuncture to send top-down anti-inflammatory commands from the brain to organs and immune cells.

2. The Cholinergic Anti-Inflammatory Pathway (CAIP)

Before around the year 2000, acupuncture’s anti-inflammatory effects were mostly explained through humoral regulation. More recently, the cholinergic anti-inflammatory pathway (CAIP) has become central in explaining how acupuncture calms inflammation.

Key points:

• Acupuncture can modulate the vagus nerve
• It exerts anti-inflammatory effects via CAIP and the vagus–adrenal medulla–dopamine pathway
• These effects are dependent on an intact vagus nerve

Examples from experimental models:

• In a Concanavalin A–induced hepatitis model, manual or electroacupuncture at ST36 (Zusanli) reduces phospho-ERK1/2 and TNF-α production in liver cells via vagal modulation. Vagotomy largely abolishes this effect.
• In sepsis-induced myocardial injury, EA at ST36 lowers TNF-α, nitric oxide (NO), neutrophil accumulation, and CK-MB activity, protecting the heart. These benefits are much weaker after vagotomy.
• In liver ischemia–reperfusion injury, EA at LI4 (Hegu) loses its protective effect when the vagus nerve is segmentally blocked, indicating segment-specific activation of CAIP.

3. ACh and α7nAChR: Core Molecules in Acupuncture’s Anti-Inflammatory Signaling

The main molecular components of CAIP are:

• Acetylcholine (ACh)
• α7 nicotinic acetylcholine receptor (α7nAChR)

In an obesity model, EA (but not manual acupuncture) enhances vagal activity, promotes ACh release, and activates α7nAChR in mesenteric white adipose tissue (mWAT), which suppresses TNF-α and improves inflammatory status.

α7nAChRs are widely distributed in the hippocampus (highest density), prefrontal cortex, basal ganglia, temporal cortex, and in peripheral immune cells such as lymphocytes and macrophages.

Selected examples of α7nAChR-mediated acupuncture effects:

• Postoperative cognitive dysfunction (POCD) after partial hepatectomy: EA at GV20, PC6, LI4 for 7 days increases α7nAChR expression and reduces TNF-α and IL-1β in hippocampal neurons, easing neuroinflammation.
• Ischemic stroke: EA at GV20 and GV24 for 7 days up-regulates α7nAChR and lowers TNF-α and IL-1β in the hippocampus, improving learning and memory.
• CPB-related acute lung injury: EA pretreatment at ST36 and BL13 restores α7nAChR-dependent cholinergic signaling and inhibits HMGB1, IL-1β, TNF-α, protecting lung tissue.
• Liver I/R injury: EA at LI4 or a non-selective nicotinic ACh receptor agonist reduces neutrophil accumulation and serum TNF-α and IL-6, with little effect on IL-10.
• Intestinal I/R injury: EA and α7nAChR agonists similarly protect the intestinal mucosa by up-regulating mucosal α7nAChR mRNA and decreasing NF-κB p65, IL-6, and TNF-α. These protective effects are reversed by α7nAChR antagonists.
• Ischemic brain injury: EA at GV20 increases α7nAChR, TGF-β1, and IL-10, while decreasing TNF-α and IL-18 to achieve neuroprotection.
• During cerebral ischemia, EA promotes microglial polarization from M1 to M2 through α7nAChR signaling, enhancing anti-inflammatory cytokine expression.

4. Muscarinic Receptors, ChAT, AChE, and JAK2/STAT3

Beyond nicotinic receptors, muscarinic receptors (M1–M5) also participate in acupuncture’s anti-inflammatory effects.

In ischemic stroke models:

• EA at GV20 and GV14 up-regulates M1–M5 in peri-infarct areas, helping protect brain tissue.
• EA also modulates choline acetyltransferase (ChAT) mRNA, helping restore the central cholinergic system.

Two downstream α7nAChR-related pathways, JAK2/STAT3 and MAPK, are crucial in inflammation:

• In chronic cerebral hypoperfusion, MA at ST36 and GV20 up-regulates α7nAChR, activates JAK2/STAT3, and decreases hippocampal TNF-α and IL-6, protecting neurons.
• Excessive JAK2/STAT3 activation is harmful. EA at GV20 and GV14 for 4 weeks reduces inflammatory injury by down-regulating overactive JAK2/STAT3 and lowering TNF-α and IL-1β.
• In neuropathic pain (SNI model), EA at ST36 and SP6 alleviates mechanical hypersensitivity, likely by activating α7nAChR, inhibiting JAK2/STAT3, and reducing TNF-α, IL-6, and IL-1β in DRG and spinal cord.

5. Respiratory System: “Reverse” Cholinergic Modulation

In the respiratory system, acupuncture shows a kind of reverse regulation of the cholinergic system.

ACh is the main transmitter of parasympathetic fibers to airway glands and smooth muscle, but it is also produced by many non-neuronal lung cells such as T/B cells, alveolar macrophages, airway epithelial cells, dendritic cells, and endothelial cells. This non-neuronal ACh contributes to the pathogenesis of COPD and asthma.

• In COPD models, EA at ST36 and BL13 down-regulates ACh and α7nAChR and strongly inhibits JAK2/STAT3 and NF-κB, improving inflammation.
• In asthma models, MA at GV14, BL12, BL13 is effective, with BL13 especially beneficial. The mechanisms include lowering ChAT, restoring impaired M1 and M2 receptors, and reducing ACh release from parasympathetic terminals, which secondarily influences AChE expression.
• In COPD patients, reductions in ACh and α7nAChR after EA treatment correlate with strong inhibition of post-receptor JAK2/STAT3 and NF-κB signaling.

These findings suggest that acupuncture can bi-directionally regulate the ACh system: enhancing cholinergic anti-inflammatory signaling in some contexts, while suppressing pathological cholinergic overactivity in diseases such as COPD and asthma.

6. Summary

Overall, acupuncture regulates the expression and activity of:

• Acetylcholine (ACh)
• α7nAChR and muscarinic receptors (M1–M5)
• ChAT and AChE
• Downstream JAK2/STAT3, NF-κB, and MAPK pathways

Through these mechanisms, acupuncture suppresses excessive pro-inflammatory cytokines, supports anti-inflammatory mediators, and protects tissues such as the brain, liver, intestines, lungs, heart, and peripheral nerves. This offers a modern neuro-immune explanation for how acupoints like ST36, LI4, BL13, GV20 can modulate inflammation via the cholinergic anti-inflammatory axis.

一、從中樞整合到「向外輸出」的抗發炎訊號

中樞神經系統（CNS）不只是接收疾病與發炎的訊息，也是 整合針灸訊號並向全身發出調節指令的核心中樞。

研究顯示，針灸可以：

• 活化腦幹內的中介神經元，尤其是孤束核（NTS）
• 啟動多條神經－免疫輸出通路，包含 膽鹼抗發炎通路（CAIP）、 迷走－腎上腺髓質－多巴胺路徑、交感神經路徑， 以及下視丘－腦垂體－腎上腺（HPA）軸等

綜合這些路徑，針灸可以將來自穴位的訊號轉換為自上而下的 抗發炎調控指令，傳遞到全身器官與免疫細胞。

二、膽鹼抗發炎通路（CAIP）

2000 年前，針灸的抗發炎效果多以體液調節來解釋。近年來， 膽鹼抗發炎通路（CAIP）逐漸成為理解針灸抗發炎的重要框架。

關鍵重點：

• 針灸可以調節迷走神經活性
• 透過 CAIP 與迷走－腎上腺髓質－多巴胺路徑發揮抗發炎作用
• 這些效應高度依賴迷走神經完整性

實驗模型中的例子包括：

• 在Concanavalin A 誘導肝炎模型中，對足三里（ST36） 施以手針或電針，可透過迷走神經調節，降低肝細胞中 phospho-ERK1/2 與 TNF-α；一旦行迷走神經切除（vagotomy），此效果明顯減弱。
• 在敗血症導致的心肌損傷中，電針 ST36 可降低 TNF-α、NO、 嗜中性球聚集與 CK-MB 活性，對心肌有保護作用；迷走神經切除後，保護效應 明顯下降。
• 在肝臟缺血再灌流（I/R）損傷中，若段落性阻斷迷走神經， 對合谷（LI4）的電針預處理就失去保護效果，顯示 不同穴位的抗發炎作用與對應節段 CAIP 的啟動有關。

三、乙醯膽鹼與 α7nAChR：針灸抗發炎的關鍵分子

CAIP 的兩大核心分子是：

• 乙醯膽鹼（ACh）
• α7 菸鹼型乙醯膽鹼受體（α7nAChR）

在肥胖大鼠模型中，電針（而非單純手針）可增強迷走神經活性， 促進 ACh 釋放，活化腸系膜白色脂肪（mWAT）中的 α7nAChR， 抑制TNF-α，並改善發炎狀態。

α7nAChR 廣泛分布於海馬（密度最高）、前額葉、基底核、顳葉皮質， 以及外周免疫細胞如淋巴球與巨噬細胞。

部分 α7nAChR 相關的針灸研究：

• 術後認知功能障礙（POCD）模型中， 對百會（GV20）、內關（PC6）、合谷（LI4）連續電針 7 天， 可增加海馬神經元中 α7nAChR，降低TNF-α、IL-1β，減少神經發炎。
• 缺血性中風模型中，電針GV20、神庭（GV24） 7 天， 可提高 α7nAChR，降低海馬內 TNF-α、IL-1β，改善學習與記憶。
• 體外循環相關急性肺損傷模型中，電針ST36、肺俞（BL13） 可恢復 α7nAChR 相關膽鹼訊號，抑制HMGB1、IL-1β、TNF-α，保護肺組織。
• 肝臟缺血再灌流中，電針LI4或給予菸鹼型 ACh 受體致效劑， 可減少嗜中性球浸潤與血清 TNF-α、IL-6，對 IL-10 影響較小。
• 腸道缺血再灌流中，電針與 α7nAChR 致效劑皆可透過增加黏膜 α7nAChR mRNA， 降低 NF-κB p65、IL-6、TNF-α，保護腸黏膜；使用 α7nAChR 拮抗劑可以逆轉此保護作用。
• 缺血性腦損傷中，電針GV20可提高 α7nAChR、 TGF-β1與IL-10，降低 TNF-α、IL-18，達到神經保護。
• 在腦缺血模型中，電針亦可透過 α7nAChR 訊號促使小膠細胞由 M1 轉為 M2 型， 增加抗發炎細胞激素，減少神經發炎。

四、蕈毒鹼受體、ChAT、AChE 與 JAK2/STAT3

除了菸鹼型受體 α7nAChR 外，蕈毒鹼型受體 M1–M5也參與針灸的抗發炎作用。

在缺血性中風模型中：

• 電針GV20、GV14可上調缺血周邊區域的 M1–M5 受體，對腦組織具有保護效果。
• 同時調節膽鹼乙醯轉移酶（ChAT） mRNA，有助於恢復中樞膽鹼能系統功能。

α7nAChR 的下游關鍵路徑包括JAK2/STAT3與MAPK：

• 在慢性腦低灌流模型中，手針ST36、GV20可上調 α7nAChR， 啟動 JAK2/STAT3，降低海馬中 TNF-α、IL-6，保護神經元。
• 過度活化的 JAK2/STAT3 會傷害腦組織。電針GV20、GV14四週， 可下調過度活化的 JAK2、STAT3，並降低 TNF-α、IL-1β，減少發炎損傷。
• 在神經病理性疼痛（SNI）模型中，電針ST36、SP6可 緩解機械性痛覺過敏，機制可能與啟動 α7nAChR、抑制 JAK2/STAT3， 並降低 DRG 與脊髓中的 TNF-α、IL-6、IL-1β 有關。

五、呼吸系統中的「反向調節」：抑制過度膽鹼活性

在呼吸系統中，針灸對膽鹼系統的調節呈現某種 「反向」特徵。

ACh 不僅是迷走副交感纖維支配氣道腺體與平滑肌的主要神經傳導物，也大量由肺部的 非神經細胞產生，如 T、B 細胞、肺泡巨噬細胞、呼吸道上皮細胞、 樹突細胞與內皮細胞等，與COPD 與氣喘的病程密切相關。

• 在 COPD 模型中，電針ST36、肺俞（BL13）可下調 ACh 與 α7nAChR， 並強力抑制JAK2/STAT3 與 NF-κB訊號，改善發炎。
• 在氣喘模型中，手針GV14、BL12、BL13具良好效果，其中以 BL13最有利於緩解症狀。機制包括降低ChAT， 修復受損的 M1、M2 受體，減少副交感神經末梢 ACh 釋放，進而影響 AChE 表達。
• 在 COPD 患者中，接受電針後 ACh 與 α7nAChR 的下降，與 JAK2/STAT3 與 NF-κB 的強烈抑制相對應。

這些研究顯示，針灸對膽鹼系統具有雙向調節能力： 在某些情境（如全身與腦部發炎）強化膽鹼抗發炎訊號，而在 COPD、氣喘等疾病中， 則抑制異常亢進的膽鹼活性。

六、小結：經由 ACh 與其受體的精細調節，完成抗發炎

綜合以上，針灸可以：

• 調節乙醯膽鹼（ACh）的產生與釋放
• 調控α7nAChR 與蕈毒鹼受體 M1–M5的表達與活性
• 間接影響ChAT、AChE這兩個與 ACh 合成與分解相關的關鍵酵素
• 進一步調整JAK2/STAT3、NF-κB、MAPK等下游訊號路徑

經由這些環節，針灸能抑制過度的促發炎細胞激素，支持抗發炎因子， 並保護腦、肝、腸道、肺、心臟與周邊神經等組織。 這也提供一個現代神經免疫的解釋，說明像足三里（ST36）、合谷（LI4）、肺俞（BL13）、百會（GV20） 等穴位，如何透過膽鹼抗發炎軸調節不同系統的發炎反應。