Bioelectronic medicine: Preclinical insights and clinical advances

Pavlov, Valentin A.; Tracey, Kevin J.

doi:10.1016/j.neuron.2022.09.003

Cited by 45 publications

(49 citation statements)

References 201 publications

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“…ACh then acts via α7 nicotinic ACh receptors (α7nAChR) expressed on macrophages to suppress the production and release of TNF and other pro-inflammatory cytokines. This endogenous reflex can also be amplified by external stimuli such as electrical stimulation, which has shown success in preclinical models of multiple inflammatory conditions (Falvey et al 2022 ; Pavlov and Tracey 2022 ). Further, this knowledge has been translated to successful clinical trials utilizing electrical/bioelectronic VNS in patients with IBD and rheumatoid arthritis (Bonaz et al 2016 ; Koopman et al 2016 ).…”

Section: Main Textmentioning

confidence: 99%

“…Further, this knowledge has been translated to successful clinical trials utilizing electrical/bioelectronic VNS in patients with IBD and rheumatoid arthritis (Bonaz et al 2016 ; Koopman et al 2016 ). This approach was first assessed and validated in these disorders due to the pronounced effect of VNS on the serum levels of TNF - a key molecular mediator of inflammation and disease pathogenesis (Falvey et al 2022 ; Pavlov and Tracey 2022 ). Preclinical research investigating the efficacy of VNS in controlling inflammation has focused on the cytokine response to stimulation.…”

Section: Main Textmentioning

confidence: 99%

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Vagus nerve stimulation and inflammation: expanding the scope beyond cytokines

Falvey

2022

Bioelectron Med

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Approximately 20 years ago it was discovered that the vagus nerve regulates pro-inflammatory cytokine levels and inflammation. Subsequent research using several preclinical models revealed that vagus nerve stimulation evokes a protective decrease in pro-inflammatory cytokines in multiple inflammatory disorders. Consequently, the pro- and anti- inflammatory cytokine balance has become the predominant readout for indicating a positive outcome of vagus nerve stimulation. However, cytokine levels are just a single aspect of an effective immune response. It is conceivable that vagus nerve stimulation regulates inflammation through additional mechanisms. In this letter, I discuss a manuscript that describes how vagus nerve stimulation promotes resolution of inflammation via regulating the balance of specialised pro-resolving mediator levels and neutrophil activity.

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Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

Vagus nerve stimulation and inflammation: expanding the scope beyond cytokines

Falvey

2022

Bioelectron Med

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“… Direct sympathetic modulation of leukocytes in the spleen has become a topic of intense interest in recent years due to the discovery of the cholinergic anti-inflammatory pathway (CAP), which provides a novel approach for activating anti-inflammatory mechanisms in the spleen (Falvey et al, 2022 , Hoover, 2017 , Kelly et al, 2022 , Pavlov and Tracey, 2022 ). This system is unique in having two unexpected cholinergic elements: 1) preganglionic vagal cholinergic input to sympathetic neurons in the celiac/superior mesenteric ganglia and 2) cholinergic T cells, which have a crucial role in non-neuronal release of acetylcholine (ACh) in the spleen.…”

Section: Introductionmentioning

confidence: 99%

“…This system is unique in having two unexpected cholinergic elements: 1) preganglionic vagal cholinergic input to sympathetic neurons in the celiac/superior mesenteric ganglia and 2) cholinergic T cells, which have a crucial role in non-neuronal release of acetylcholine (ACh) in the spleen. Stimulation of vagal efferent fibers activates spleen projecting sympathetic neurons in the celiac/superior mesenteric ganglia (Hoover, 2017 , Kressel et al, 2020 , Lehner et al, 2019 , Murray et al, 2019 , Murray et al, 2021 , Pavlov and Tracey, 2022 ). These nerve fibers travel to the spleen in the splenic nerve, which enters the organ at the hilum with the splenic artery (Bellinger et al, 1989 , Felten et al, 1985 , Sokal et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Activation of these fibers by vagal stimulation induces release of norepinephrine (NE) from varicosities, and stimulation of β 2 -adrenergic receptors on a subset of cholinergic CD4 + T cells by NE causes local release of ACh (Rosas-Ballina et al, 2011 , Sokal et al, 2021 , Vida et al, 2011a , Vida et al, 2011b ). Next, T cell derived ACh diffuses to macrophages located in the marginal zone and possibly other sites in the spleen, where it evokes an anti-inflammatory response through activation of α7 nicotinic ACh receptors (Hoover, 2017 , Pavlov and Tracey, 2022 , Wang et al, 2003 ). Specifically, α7 activation inhibits the production and release of proinflammatory cytokines such as tissue necrosis factor-α and interleukin-6.…”

Section: Introductionmentioning

confidence: 99%

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Sympathetic innervation of human and porcine spleens: implications for between species variation in function

et al. 2022

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Background The vagus nerve affects innate immune responses by activating spleen-projecting sympathetic neurons, which modulate leukocyte function. Recent basic and clinical research investigating vagus nerve stimulation to engage the cholinergic anti-inflammatory pathway (CAP) has shown promising therapeutic results for a variety of inflammatory diseases. Abundant sympathetic innervation occurs in rodent spleens, and use of these species has dominated mechanistic research investigating the CAP. However, previous neuroanatomical studies of human spleen found a more restricted pattern of innervation compared to rodents. Therefore, our primary goal was to establish the full extent of sympathetic innervation of human spleens using donor tissue with the shortest procurement to fixation time. Parallel studies of porcine spleen, a large animal model, were performed as a positive control and for comparison. Methods Human and porcine spleen tissue were fixed immediately after harvest and prepared for immunohistochemistry. Human heart and porcine spleen were stained in conjunction as positive controls. Several immunohistochemical protocols were compared for best results. Tissue was stained for tyrosine hydroxylase (TH), a noradrenergic marker, using VIP purple chromogen. Consecutive tissue slices were stained for neuropeptide Y (NPY), which often co-localizes with TH, or double-labelled for TH and CD3, a T cell marker. High-magnification images and full scans of the tissue were obtained and analyzed for qualitative differences between species. Results TH had dominant perivascular localization in human spleen, with negligible innervation of parenchyma, but such nerves were abundant throughout ventricular myocardium. In marked contrast, noradrenergic innervation was abundant in all regions of porcine spleen, with red pulp having more nerves than white pulp. NPY stain results were consistent with this pattern. In human spleen, noradrenergic nerves only ran close to T cells at the boundary of the periarterial lymphatic sheath and arteries. In porcine spleen, noradrenergic nerves were closely associated with T cells in both white and red pulp as well as other leukocytes in red pulp. Conclusion Sympathetic innervation of the spleen varies between species in both distribution and abundance, with humans and pigs being at opposite extremes. This has important implications for sympathetic regulation of neuroimmune interactions in the spleen of different species and focused targeting of the CAP in humans.

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Organ Neuroprosthetics: Connecting Transplanted and Artificial Organs with the Nervous System

Micera,

Menciassi,

Cianferotti

et al. 2024

Adv Healthcare Materials

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Implantable neural interfaces with the central and peripheral nervous systems are currently used to restore sensory, motor, and cognitive functions in disabled people with very promising results. They have also been used to modulate autonomic activities to treat diseases such as diabetes or hypertension. Here, this study proposes to extend the use of these technologies to (re‐)establish the connection between new (transplanted or artificial) organs and the nervous system in order to increase the long‐term efficacy and the effective biointegration of these solutions. In this perspective paper, some clinically relevant applications of this approach are briefly described. Then, the choices that neural engineers must implement about the type, implantation location, and closed‐loop control algorithms to successfully realize this approach are highlighted. It is believed that these new “organ neuroprostheses” are going to become more and more valuable and very effective solutions in the years to come.

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Bioelectronic medicine: Preclinical insights and clinical advances

Cited by 45 publications

References 201 publications

Vagus nerve stimulation and inflammation: expanding the scope beyond cytokines

Vagus nerve stimulation and inflammation: expanding the scope beyond cytokines

Sympathetic innervation of human and porcine spleens: implications for between species variation in function

Organ Neuroprosthetics: Connecting Transplanted and Artificial Organs with the Nervous System

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