Electroceutical Therapy for Autoimmune Disease

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This entry is adapted from the peer-reviewed paper 10.3390/ph16081089

Continuous dialogue between the immune system and the brain plays a key homeostatic role in various immune responses to environmental cues. Several functions are under the control of the vagus nerve-based inflammatory reflex, a physiological mechanism through which nerve signals regulate immune functions. In the cholinergic anti-inflammatory pathway, the vagus nerve, its pivotal neurotransmitter acetylcholine, together with the corresponding receptors play a key role in modulating the immune response of mammals. Bioelectronic medicine has recently emerged as an alternative approach to managing systemic inflammation. Nerve electrostimulation was reported to be clinically relevant in reducing chronic inflammation in autoimmune diseases, including rheumatoid arthritis and diabetes.

electroceutical therapy inflammation autoimmune disease

1. Introduction

Homeostatic adaptations and responses to challenging or adverse environmental insults require engagement of both the immune system and the nervous system that interact through several means. Key to these regulations is the ongoing dialogue between the two systems mediated by soluble molecules derived from both neurons and immune cells, and sensory nerves of the autonomic nervous system ^[1]^[2]. In the central nervous system (CNS), the interplay between nerve fibers and inflammatory mediators has been well documented. Microglial cells express Toll-like receptors (TLRs), allowing for communication between the immune system and the brain ^[3]. For example, injection of bacterial lipopolysaccharides (LPS) stimulates nerve signaling in a TLR4-dependent manner ^[4], and subdiaphragmatic vagotomy mitigates fever triggered by administration of cytokines, namely IL-1β or LPS ^[5].

In the periphery, cytokines and pathogen-associated molecular patterns stimulate the afferent vagus nerve (VN). The resulting signals navigate through the nucleus tractus solitarius and the dorsal motor nucleus of the VN and are then propagated to the splenic nerve in the celiac plexus. In these vagal interactions with the immune system, the spleen, despite lacking parasympathetic fibers, plays a key role by hosting immune cells that express adrenergic receptors able to interact with norepinephrine (NE) derived from sympathetic nerves ^[6]. NE conveys multiple cross-talks with sympathetic nerves, namely the alpha- (α-AR) and beta-adrenergic receptor (β-AR) that exert effects in opposite directions. Whereas αARs have stimulatory functions, βARs are inhibitory and exhibit an overall predominant effect. Interaction of NE with β2-adrenergic receptors (β2-ARs) present on lymphocytes causes them to release acetylcholine (ACh), providing a link between NE and immunosuppression (Rosas-Ballina, 2011 #41; Fujii, 2017 #65). ACh binding to the α7 nicotinic ACh receptor (α7nAChR) present on inflammatory cells triggers signal transduction pathways that culminate in the reduction of proinflammatory cytokine production by the spleen, including TNF-α, IL-1β, and IL-6 ^[7]^[8]^[9], but not the anti-inflammatory cytokine IL-10 ^[10]^[11]. Overall, the sympathetic nervous system downmodulates immunity, essentially through production of NE, able to inhibit production of proinflammatory cytokines, and to reduce chemotaxis and phagocytosis of neutrophils ^[12]. Thus, through releasing ACh, the VN exerts anti-inflammatory effects.

In pathological conditions, inflammatory signals emanating from peripheral organs reach the CNS via the afferent VN. In turn, the efferent arm of this neuroimmune reflex, termed the cholinergic anti-inflammatory pathway (CAP), is initiated through activation of the splenic nerve, leading to the release of the pivotal neurotransmitter ACh from splenocytes. As a result, the ACh produced activates cholinergic receptors, namely the α7nAChR, which mitigates production of proinflammatory cytokines ^[13]^[14]. Converging studies indicate that activation of this pathway mitigates production of proinflammatory cytokines and suppresses systemic inflammation ^[10]^[11]. As discussed here, stimulation of this anti-inflammatory pathway can be targeted for therapeutic purposes in several chronic autoimmune diseases (AID), such as rheumatoid arthritis (RA).

2. Electroceutical Therapy for Autoimmune Disease

2.1. Rheumatoid Arthritis

Standard therapies for RA include pharmacological agents that target inflammatory processes, but a number of patients are not responsive to treatment and suffer from impairments in the quality of life. The inverse relationship between VN activity, as assessed by HRV, and serum levels of inflammatory markers indicates a potential link between insufficient vagal activity and inflammatory processes ^[15]. There is also evidence that the reduced vagal activity precedes RA development in at-risk patients ^[16]. Notably, the α7nAChR is detectable in synovial lining cells of RA patients, including macrophages and fibroblast-like synoviocytes (FLS). Therefore, the imbalance in sympathetic/parasympathetic pathways could underly a defective release of ACh capable of binding to the α7nAChR present on inflammatory cells and FLS of the joints. Ex vivo, ACh is capable of significantly reducing the production of cytokines and inhibiting the release of CXCL8, CCL2, CCL3, and CCL5 from IL-1β-stimulated FLS ^[17]. Consequently, the resulting uncontrolled release of proinflammatory cytokines would promote inflammation in the joint and cartilage erosion ^[16]^[18].

Collagen-induced arthritis (CIA) exhibits characteristics reminiscent of the human disease, including inflammation, pannus formation, joint swelling, cartilage destruction, bone erosion, and production of proinflammatory cytokines in the serum. In CIA of the rat, expression of the gene encoding α7nAChR (CHRNA7) is increased, and its inactivation mitigates inflammation ^[19]. In early studies, treatment with pharmacological agents (nicotine or selective agonists of α7nAChR (AR-R17779, or GTS-21)) reduced clinical signs of arthritis and TNF-α expression in the synovium, improved bone erosion and cartilage loss, and lowered serum levels of proinflammatory cytokines ^[20]. Reversibly, disease severity was aggravated by vagotomy or genetic deletion of the α7nAChR ^[21].

In experimental models of arthritis, electrical stimulation of the VN reduced disease progression, and vagotomy aggravated disease symptoms by enhancing neutrophil migration (Kanashiro, 2016 #82). In the rat, direct activation of the CAP by VNS reduced inflammation, joint swelling, cytokine production, and synovitis, and mitigated cartilage destruction and periarticular bone resorption ^[22]. In male Wistar rats, vagal stimulation reduced neutrophil migration and arthritic joint inflammation by activating specific sympathoexcitatory brain nuclei in the locus coeruleus and the paraventricular hypothalamic nucleus ^[23]. It also led to increased NE levels in the synovial fluid and reduction of synovial inflammatory cytokines. In studies of CIA in female Dark Agouti rats, abdominal VNS reduced disease manifestations, and the treatment diminished systemic levels of RANKL, TNF-α, and histological scores of inflammation and cartilage damage ^[24]. There was also less infiltration of inflammatory cells. However, this model is not representative of patients suffering from drug-resistant RA. Studies of adjuvant-induced arthritis, which includes more severe bone erosion, would be suitable for validating the utility of abdominal VNS and its potential to reduce off-target effects of cervical stimulation.

Noninvasive US energy delivered to the abdomen of mice during renal ischemic reperfusion injury was reported to reduce inflammation and tissue damage. Remarkably, the anti-inflammatory effects were mediated by T and B lymphocytes ^[25], and transfer of leukocytes from US-treated spleens to naïve recipient mice could confer protection ^[26]. In further experiments, daily noninvasive US stimulation that targets the spleen was reported to reduce disease severity in the K/BxN serum-transferred model of inflammatory arthritis ^[27]. Importantly, both T and B cell populations were involved in the anti-inflammatory pathway, indicating that US stimulation of the spleen has the potential to treat inflammatory diseases. Collectively, these observations suggest that the cholinergic anti-inflammatory pathway can be targeted by direct stimulation of α7 receptors through US and VN stimulations.

In patients suffering from RA, the observation that the α7nAChR plays an important role in the release of inflammatory cytokines and regulation of inflammatory response suggests that vagal electrical stimulation could represent a promising alternative therapy ^[28]. In a clinical trial, VNS was used to treat RA using implantable vagus nerve electrode cuffs that delivered an electrical current (up to 2.0 mA) to the cervical VN for 60 s one to four times daily ^[16]. VNS inhibited TNF-α production for up to 84 days and reduced disease severity ^[16]. Remarkably, suppression of TNF-α release during VNS was observed only when the implantable medical device was functioning. In drug-resistant RA patients, approximately 70% of subjects experienced disease improvement ^[16].

During cervical VNS, patients may report voice alterations and coughing, and cardiac and respiratory undesirable effects ^[29]. These side effects are likely due to the fact that the human cervical vagus nerve, which consists of 99% C-fibers at the abdominal level, comprises 80% C-fibers and 20% A- and B-fibers ^[30]. Stimulation of these latter fibers, characterized by low electrical threshold, can cause activation of the heart, lungs, and larynx ^[31]. Therefore, more specifically targeting the nerve fiber subset responsible for therapeutic effects would improve efficacy of electroceutical treatment ^[24]. In a clinical trial, the anti-inflammatory effects of short-term transcutaneous noninvasive VNS (n-VNS) applied to the cervical VN were evaluated in patients with RA ^[32]. The treatment was well tolerated and provided preliminary support for this therapeutic strategy in patients with RA. However, further investigations using larger placebo-controlled trials are warranted.

An alternative means to stimulating the VN is to apply electrical signals to the cutaneous region supplied by the auricular branch of the VN. In a cohort of RA patients, application of a vibrotactile device to the cymba concha of the external ear reduced peripheral blood production of TNF-α, IL-1β, and IL-6, and alleviated systemic inflammatory responses ^[33]. The disease attenuation observed persisted for up to seven days in the majority of RA patients. These observations deserve further attention. Prospectively, in parallel to the use of biologics for the treatment of RA, studies on VNS could provide additional benefits to patients affected with this autoimmune disease, such as amelioration of depression and reduction of chronic pain ^[34]^[35].

2.2. Lupus

Autonomic function tests, including cardiovascular and HRV, have been used to probe autonomic dysfunctions in the autoimmune disease systemic lupus erythematosus (SLE). They revealed differences, when compared to normal subjects ^[36]. The autonomous nervous system dysfunction, with a prevalence of the sympathetic activity, was associated with a decreased parasympathetic tone and an increase in proinflammatory cytokines ^[37]. This alteration weakens the VN-mediated anti-inflammatory reflex and, possibly, promotes autoimmunity development. It indicates that the VN is hypoactive. Hence, stimulation of this pathway could alleviate the exacerbated release of inflammatory mediators and reduce inflammation in SLE.

In early studies, nicotine and other cholinergic agonists have been found to significantly reduce the production of proinflammatory mediators through the α7nAChR in models of ischemia perfusion injury ^[38], but also in experimental models of sepsis and pregnancy-induced hypertension ^[13]^[39]. In experimental studies on hypertension-prone lupus mice, administration of nicotine (2 mg/kg/day, subcutaneously) was used to stimulate the CAP at the level of the splenic α7nACh. This treatment reduced hypertension and was associated with lower expression of proinflammatory cytokines in the spleen and the kidney, suggesting that the CAP is impaired in lupus ^[40].

In patients with lupus nephritis, the expression of inflammatory cytokines (TNF-α, IL-1β, and IL-6) is high, and an α7nAChR agonist decreases the levels of these inflammatory mediators. The view that stimulation of the parasympathetic VN using transcutaneous stimulation (tVNS) could be useful in reversing the consequences of autoimmune manifestations has been tested in the human disease. In a randomized, double-blinded, sham-controlled pilot study of 18 patients with lupus, pain, fatigue, and number of swollen joints were significantly reduced following four days of five-minute transcutaneous auricular VNS ^[41]. However, the effects on other markers of inflammation and disease activity were not documented. Thus, the use of neuromodulation-based bioelectronic medicine for SLE treatment is in its infancy, but further trials could lead to promising options to alleviate lupus symptoms and potentially reverse the disease ^[42].

2.3. Scleroderma

Systemic sclerosis (SSc), also called scleroderma, is a rare systemic autoimmune disorder characterized by typical skin thickening and involvement of several major organs, including the lung, heart, kidney, and GI tract. The autonomic nervous system controls saliva production via the functional M3 muscarinic acetylcholine receptor (M3R) on acinar cells, and deficiency of the M3 mAChR in mice results in hyposalivation. In initial studies, muscarinic agonists (pilocarpine and cevimeline) were reported to stimulate expression of both M1 and M3 receptors in salivary glands and to promote secretory function ^[43]^[44]. In addition to inflammatory responses, SSc patients suffer from fatigue, anxiety, and depression, and dysfunction of the autonomous nervous system could account, at least in part, for some clinical manifestations. In a trial of 17 SSc patients with upper GI tract dysfunction, prolonged use of tVNS resulted in normalization of the sympathovagal balance and improvement in GI symptom score ^[45]. More recently, noninvasive VNS was reported to reduce levels of inflammatory cytokines (IL-6, IL-1β, and TNF-α) in SSc patients ^[46], suggesting that receptor agonists and VNS could be used to treat this autoimmune disorder.

2.4. Diabetes

In type 2 diabetes, stimulation of parasympathetic nerves could modulate β-cells of the pancreas to increase insulin secretion and reduce pathogenesis. In type 1 autoimmune diabetes (T1D), however, β-cells are eventually destroyed by autoreactive lymphocytes. In a diabetes mouse model triggered by streptozotocin, administration of a specific acetylcholinesterase inhibitor prevented hyperglycemia, reduced lymphocyte infiltration into pancreatic islets and preserved the structure and functionality of β-cells, and suppressed production of IL-1β, IL-6, and IL-17 proinflammatory cytokines ^[47]. The observation that cholinergic stimulation can prevent disease development provides a promising preventive strategy for T1D. Modulation of autoimmune disease severity by administration of AChE inhibitors deserves further attention.

Electrostimulation of autonomic nerves has been demonstrated to block inflammation via the neurotransmitters NE and ACh ^[28]. However, stimulation of large nerves, such as the VN, can exhibit undesirable side effects on multiple organs. Since autoreactive lymphocytes are activated in pancreatic lymph nodes before migrating to the adjacent pancreas to destroy β-cells in patients with T1D, investigators targeted draining lymph nodes by nerve electrical stimulation. Electrostimulation treatment reduced proliferation of autoreactive lymphocytes and production of proinflammatory cytokines, but also inhibited progression of autoimmune diabetes ^[48]. All these effects were mediated by activation of β-adrenergic receptors. The fact that pancreatic nerve electrical stimulation mitigates diabetes progression in a mouse model of T1D ^[48] suggests that electrical stimulation of peripheral nerves for therapeutic purposes, called electroceuticals or bioelectronics, represents a future potential approach for treating AID. Since this electroceutical approach targets the disease triggers rather than the symptoms, it would represent an important shift in T1D therapeutics.

In another hyperglycemic rodent model induced by streptozotocin combined with a high-fat diet, VNS delivered through electrodes implanted at the dorsal subdiaphragmatic vagus resulted in reduction of blood glucose in diabetic rats by enhancing vagal efferent activity and the release of glucagon-like peptide-1 ^[49]. To gain further insight into the underlying mechanisms, more recent studies applied electrical stimulation to a branch of the VN that only innervates the pancreas ^[50], thereby abrogating the confounding effects of modulation of liver function, nutrient absorption, and gastric motility on blood glycemia. In a model of streptozotocin-induced diabetes, implantation of a cuff electrode on the pancreatic branch of the VN, followed by electrical stimulation, had protective effects by reducing deficits in Langerhans islet diameter, and ameliorated insulin loss ^[50]. However, the disease manifestations were monitored only during a snapshot of the disease, which is unlikely to reflect the complex physiopathology of T1D ^[50], an autoimmune disease characterized by a progressive and continuous attack that ultimately destroys the β-cells. Additionally, there are marked differences in the structure and innervation patterns of the islet between rodents and humans. Therefore, additional studies are required using experimental models that more faithfully mimic the anatomy of human Langerhans islets and disease progression of T1D.

2.5. Inflammatory Bowel Diseases

Persistent bowel inflammation in IBD, including ulcerative colitis and Crohn’s disease, is associated with alterations of innate and adaptive immune responses, but also with dysfunction of the enteric nervous system and the gut–brain axis ^[51]. In Crohn’s disease, drugs that modulate the symptoms by reducing the immune response or inflammation, including corticosteroids and monoclonal antibodies or bioengineered receptors targeting inflammatory cytokines, are not always effective. As a result, a significant proportion of patients are refractory to available conventional treatment options ^[52].

In addition to acting as an important site for immune surveillance, the GI tract is also an important target for efferent projections from the VN, initially emanating from cholinergic neurons located in the brainstem. Input from the VN to the GI tract can also modulate immune homeostasis in the gut by acting directly through enteric cholinergic neurons, with efferent VN-based mechanisms regulating immune responses through α7nAChR signaling. In experimental colitis, accumulating evidence indicates that nicotinic receptors mediate vagal anti-inflammatory response. In mice suffering from colitis, the acetylcholinesterase inhibitor galantamine and a muscarinic acetylcholine receptor agonist activate the central anti-inflammatory cholinergic pathway, leading to a reduction in mucosal inflammation and proinflammatory cytokine levels ^[53]. Splenectomy, vagotomy, or splenic neurectomy abrogated this cholinergic anti-inflammatory effect. In another experimental colitis model, treatment with a partial agonist at the α7nAChR (encenicline) reduced cell infiltration into the mucosa and submucosa, including macrophages, neutrophils, and B cells ^[54]. In the rat, pretreatment with cholinesterase inhibitors (neostigmine or physostigmine) or VNS mitigated colitis severity by acting through the spleen rather than directly in the gut ^[55]^[56].

In humans, it is intriguing that cigarette smoking has beneficial effects in ulcerative colitis, but aggravating effects in Crohn’s disease ^[56], probably as a result of the nicotine content of tobacco. Evidence for a beneficial effect of VNS in Crohn’s disease comes from studies of patients with moderate-to-severe disease who manifested clinical, biological, and endoscopic improvement after six months of VNS, and a reduction in inflammation of colonic tissues ^[57].

2.6. Primary Sjögren’s Syndrome

One of the most important symptoms in patients suffering from primary Sjögren’s syndrome (pSS) is chronic fatigue, and autonomic nervous system dysfunction has been reported in these patients ^[58]. The effects of noninvasive VN activation on immune responses and clinical symptoms of pSS were tested in a cohort of 15 female patients using a handheld, battery powered device that sends electrical signals to activate the VN through the skin and soft tissue of the neck. Patterns of natural killer cells and T cells were altered significantly over the study period ^[46]. Interestingly, lymphocyte counts at baseline visit correlated with the reduction in fatigue score. In a more recent trial, 40 participants suffering from pSS were randomly assigned to use active or sham noninvasive VNS devices twice daily for 54 days in a double-blind manner ^[59]. At day 56, significant improvements in three measures of fatigue were observed only in patients using the active device.

2.7. Postural Orthostatic Tachycardia Syndrome (POTS)

This condition refers to a heterogeneous autonomic disorder characterized by excessive orthostatic tachycardia in the absence of orthostatic hypotension ^[60]. Its origin remains under investigation, and a number of underlying physiopathological mechanisms have been proposed, including autoimmune reactions ^[61]. In support of autoimmune-mediated pathways in POTS is the identification in a subgroup of patients expressing serum antiadrenergic autoantibodies capable of exerting direct agonist and allosteric effects that alter receptor function ^[62]. Consistently, induction of antibodies with similar functional properties in a rabbit experimental model could trigger a hyperadrenergic POTS phenotype ^[63].

Management of this syndrome remains challenging because pharmacologic agents have limited efficacy or side effects. Recently, a noninvasive approach to stimulating the auricular branch of the VN, termed low-level tragus stimulation (LLTS), was demonstrated to improve cardiovascular autonomic function and suppress inflammation in both animal models and humans ^[64]. In an established rabbit model of adrenergic autoantibody-induced POTS, transcutaneous LLTS was found to suppress postural tachycardia, improve the sympathovagal balance—including increased acetylcholine secretion—and attenuate the expression of inflammatory cytokines ^[65]. The observation that LLTS ameliorated autoantibody-induced autonomic dysfunction and inflammation suggests that noninvasive stimulation could offer a novel, effective, safe neuromodulatory therapeutic strategy for patients with POTS, particularly those suffering from the hyperadrenergic subtype.

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