Here, we reported our original study that auricular concha stimulation is also a potent anti-inflammatory stimulus that can modulate immune factors in endotoxemia rat model. The present study demonstrates that ta-VNS may have an important role in suppressing inflammatory responses, and this contributes to the involvement of the cholinergic anti-inflammatory pathway in the mechanism.
Previous study demonstrated that the cholinergic anti-inflammatory pathway is a α
7nAChR-dependent, vagus nerve-mediated pathway [1
]. It can inhibit macrophage activation through parasympathetic outflow, which functions as an anti-inflammatory pathway in systemic and local inflammation. Inflammatory signals stimulate sensory fibers that ascend in the vagus nerve to synapse in the NTS and then activate efferent fibers in the vagus nerve to suppress peripheral cytokine release through alpha7nAChR.
The most important cytokine involved is TNF-α
, which activates other proinflammatory cytokines such as IL-1β
, IL-6, and high mobility group B1 (HMGB1) and amplifies other inflammatory mediators. VNS has been demonstrated to inhibit proinflammatory cytokine production [23
], especially the release and synthesis of TNF-α
. The present study indicates that VNS decreases LPS-induced TNF-α
, IL-1, and IL-6 in circulation. And ta-VNS reduced the levels of proinflammatory cytokines TNF-α
, and IL-6, which is similar to the effect of VNS. After administration of α
7nAChR antagonist α
-BGT, ta-VNS failed to attenuate serum TNF-α
level, which is consistent with previous reports [6
]. This result indicated that α
7nAChR played a critical role in anti-inflammatory effect of ta-VNS. The present study also demonstrated that vagotomy exacerbated serum TNF responses to inflammatory stimulation, sensitized animals to the lethal effects of endotoxin, and abolished the anti-inflammatory effect of ta-VNS. The results indicated that ta-VNS fails to suppress excessive cytokine response characterized by exaggerated TNF-α
level if there is deficiency in either the α
7nAChR subunit or vagus nerve.
B is a master transcription factor controlling the expression of a wide range of proinflammatory genes [26
]. Previous studies reported that NF-κ
B is involved in TNF-α
genetic activation and TNF-α
]. In the present study, both western blot data and immunehistochemical results indicated that ta-VNS suppresses the LPS-induced NF-κ
B expression in rat lung tissue (Figures and ), which mimicking the effects of VNS [25
]. In vagotomy animals, ta-VNS failed to inhibit increased NF-κ
B expression, suggesting ta-VNS functions in situations that require intact vagus nerve.
Some investigators demonstrated that electroacupuncture (EA, on ST36, PC6, and GV20) could increase the vagal activity of experimental animals and human subjects [13
]. The present study demonstrated that TEAS on ST36 decreased serum TNF-α
level in endotoxemia rats. After pretreatment with vagotomy or α
7nAChR antagonist α
-BGT, TEAS failed to inhibit serum proinflammatory level in LPS-induced endotoxemia animals.
Auricular acupuncture, as a special form of acupuncture, has been used for the treatment of different disorders for centuries in China. Our research group previously demonstrated that auricular acupuncture stimulation could activate neurons of NTS and upregulate vagal tune, to decrease MAP and HR [35
], to trigger gastric motility [36
]. Our previous studies also demonstrated that TEAS of auricular concha could activate the parasympathetic nervous system and mimic the effect of VNS to suppress epileptic seizures [18
]. In the present study, the results showed that ta-VNS inhibited proinflammatory cytokine levels and suppressed NF-κ
B expressions in endotoxaemia rats (Figures , , and ), which is similar to the effect of VNS. However, vagotomy or α
7nAChR antagonist α
-BGT could diminish the effect of ta-VNS on the anti-inflammatory responses, suggesting that auricular acupuncture may perform an anti-inflammatory effect via cholinergic anti-inflammatory pathway.
In general (), VNS directly activates the cholinergic anti-inflammatory pathway via stimulating efferent vagus nerve. As the peripheral branch [18
], auricular branch of vagus nerve (ABVN) innervates the auricular concha and the external auditory meatus. Stimulation of the ABVN region could evoke parasympathetic excitation [37
]. Acupuncture in the area of auricular concha may increase discharge of NTS [18
], as the central terminal nuclear for afferent vagal fibers, which primarily transmit signals from local inflammation lesion [4
]. Thus, we hypothesize that ABVN could be evoked by ta-VNS, and the activated signals ascend with vagal input to the NTS. The signals are processed within the NTS, and the integrated output signal is carried by efferent vagus nerve to inhibit inflammatory responses. TEAS on the acupoint of ST36 activates the somatic fiber endings around ST36 point, which send the acupuncture signals to the spinal cord via somatic sensory nerve fibers. In the spinal cord, the nerve impulses are delivered to the NTS by the secondary order neurons, where the signals were processed. Ultimately, the increased efferent vagal output activates the cholinergic anti-inflammatory pathway.
Figure 8 The anti-inflammatory mechanisms of the three interventions used in the present study might be as follows: (1) VNS directly activates the cholinergic anti-inflammatory pathway via stimulating efferent vagus nerve. (2) ta-VNS evoked the activity of the (more ...)