An anti-inflammatory neural circuit
The vagus nerve is the main component of the parasympathetic nervous system and innervates most of the thoracic and abdominal organs. Afferent (sensory) vagal neurons, cell bodies of which reside in the jugular and nodose ganglion, terminate in the brainstem nucleus tractus solitarius (NTS). Efferent (motor) vagus preganglionic neurons originate in the brainstem dorsal motor nucleus of the vagus and innervate visceral organs. Efferent vagus preganglionic and postganglionic neurons are primarily cholinergic, using acetylcholine as the major neurotransmitter. The NTS sends viscerosensory information to the dorsal motor nucleus of the vagus to influence the functioning of vagal efferent fibers through vagovagal reflexes.
In addition to mechanical and chemical stimuli from visceral organs, afferent vagal neurons convey inflammatory status in tissues to the NTS by sensing cytokines and other inflammatory products, which in turn activates efferent vagal neurons through the vagovagal reflex.
Electrical or pharmacologic stimulation of efferent vagal neurons in rodents was found to inhibit the systemic increase in levels of proinflammatory cytokines and prevent the development of septic shock after administration of LPS.
This neural pathway involving vagal efferents was termed the “cholinergic anti-inflammatory pathway” (Fig 1).
The reflex activation of vagal efferents by inflammatory insults and its anti-inflammatory effects led to the concept of the inflammatory reflex, a vagovagal reflex circuit that suppresses excessive inflammation and minimizes tissue damage.
The anti-inflammatory action of the vagus nerve in the animal model of sepsis depends on the presence of the spleen and sympathetic splenic nerves that produce noradrenaline as the major neurotransmitter.
Because the vagus nerve does not innervate lymphoid organs, including the spleen,
it was proposed that vagal preganglionic neurons synapse with postganglionic adrenergic neurons that supply the spleen.
In line with this idea, a fraction of CD4+ T cells in the spleen were found to produce acetylcholine in response to noradrenaline and mediate the anti-inflammatory effects of vagal efferent activation.
Acetylcholine binding to the nicotinic acetylcholine receptor subunit α7 on macrophages activates the signaling pathway involving Janus kinase 2–signal transducer and activator of transcription 3 and inhibits cytokine production, which is considered the major effector mechanism of the cholinergic anti-inflammatory pathway.
Electrotherapy for inflammatory diseases
Vagus nerve stimulation (VNS) has been accepted as a therapy for drug-resistant epilepsy and depression since the 1990s and is being investigated for the control of pain, Alzheimer disease, and cerebellar tremor.
Additionally, researchers are now attempting to use VNS for the treatment of inflammatory diseases by activating the cholinergic anti-inflammatory pathway. VNS is performed typically with an electrode wrapped around the left cervical vagus nerve, which is connected to a pulse generator surgically implanted in the chest wall. The left vagus nerve is chosen to avoid the influence on heart rate because the cardiac pacemaker sinoatrial node is innervated by the right vagus nerve. The most common adverse events are hoarseness, paresthesia, headache, and shortness of breath, but they are typically mild and decrease over time.
Currently, a noninvasive technique for VNS, which does not require surgical implantation of the electronic device, is also available.
This technique is based on transcutaneous stimulation of the auricular or carotid vagus nerve.
Recently, results from 2 clinical studies of VNS in patients with rheumatoid arthritis
and Crohn disease
were published and demonstrated the therapeutic potential of this approach. VNS through an implanted electronic device attenuated disease severity in 12 of 17 patients with rheumatoid arthritis, which was accompanied by a reduction in serum levels of proinflammatory cytokines.
In a study involving 7 patients with Crohn disease, 5 patients experienced clinical and endoscopic remission of intestinal inflammation after 6 months of VNS.
Because these therapeutic effects of VNS were achieved at lower-frequency stimulation than for epilepsy (5-10 vs 20-30 Hz), adverse events were even milder.
The effect of VNS in patients with epilepsy and depression is mediated by vagal afferents, whereas the effect in the treatment of inflammatory diseases is considered to be mediated by efferent fibers.
However, the neural circuits by which VNS suppresses inflammation in the joints and intestine are not yet well understood. Before bringing VNS to the clinic, it would be important to clarify the mechanism of its action and optimize the stimulation parameters, including current intensity, frequency, pulse width, and on-duty/off-duty cycles.
Prospects and challenges
Before the description of the cholinergic anti-inflammatory pathway, substantial evidence indicated that lymphoid organs are innervated by the sympathetic nervous system and the principal sympathetic neurotransmitter noradrenaline directly acts on immune cells primarily through β2-adrenergic receptors, which are predominantly expressed on immune cells among adrenergic receptor subtypes.
It appears that sympathetic inputs to immune cells suppress inflammatory responses in tissues. Stress-induced activation of the sympathetic nervous system in a rat model of septic shock was shown to reduce proinflammatory cytokine levels in the spleen, which was consistent with the impaired LPS responsiveness of noradrenaline-treated macrophages.
In a mouse model of allergic dermatitis, we demonstrated that activation of β2-adrenergic receptors on pathogenic T cells inhibited their recruitment to the skin and attenuated cutaneous inflammation, which was accompanied by sequestration of these T cells in lymph nodes.
Although the sympathetic and parasympathetic nervous systems generally exert opposite influences on organ functions, the findings described above suggest that both autonomic nervous systems could suppress immune functions in the context of inflammation. However, although anti-inflammatory actions of the vagus nerve have been observed on its electrical or pharmacologic stimulation, the physiologic relevance of these findings remains to be established. Furthermore, an electrophysiologic study suggested that the efferent arm of the inflammatory reflex triggered by systemic LPS administration was a conventional sympathetic pathway involving the splanchnic and splenic nerves, disputing the originally proposed parasympathetic pathway.
Thus, comprehensive understanding of the individual roles of and crosstalk between the autonomic nervous systems in the control of immune responses warrants further investigation on the neuroanatomy and immunologic targets in the immunomodulatory neural circuits.