Identification of cytokine-specific sensory neural signals by decoding murine vagus nerve activity

Zanos, Theodoros P.; Silverman, Harold; Levy, Todd; Tsaava, Téa; Battinelli, Emily; Lorraine, Peter W.; Ashe, Jeffrey; Chavan, Sangeeta S.; Tracey, Kevin J.; Bouton, Chad

doi:10.1073/pnas.1719083115

Cited by 160 publications

(170 citation statements)

References 76 publications

(105 reference statements)

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“…In agreement with our recent results 21,22 , administration of IL-1 to wild-type mice induces afferent vagus neuronal signal propagation ( Fig. 3a, 3c, and Supplemental Data Fig.…”

supporting

confidence: 93%

“…The core body temperature was monitored with a rectal probe and was maintained around 37°C with a heating pad and heat lamp. The vagus nerve was then exposed and placed on the recording electrode as described previously 22,26 .…”

mentioning

confidence: 99%

“…Optopharmacological stimulation of the vagus nerve: Mice were induced with general anesthesia using isoflurane at 2.5% in 100% oxygen at a flow rate of 1 L/min and maintained in supine position at 2.0% isoflurane. The left vagus nerve was surgically exposed as described previously 22,26 .Optovin (2 µl of 15 mM) was directly applied on the nerve 2 minutes prior to light stimulation. Animals were subjected to 405 nm light stimulation (1000 mA, 10 hz, with a 10% duty cycle for 5 minutes with an approximate power of 80-85 µW) using Thor Labs LED driver DC4100, with a 405 nm LED model M405L3 (Newton, New Jersey).…”

mentioning

confidence: 99%

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Transient Receptor Potential Ankyrin 1 Mediates Afferent Signals in the Inflammatory Reflex

Silverman

Gunasekaran

Chang

et al. 2019

Preprint

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Survival of an organism requires mechanisms to sense damaging factors in the environment. In mammals, bacterial toxins and inflammatory mediators stimulate nociceptive sensory neurons to activate protective reflexes. Whereas the vagus nerve reflex circuit that protects against damaging inflammation, termed the "inflammatory reflex," was described more than twenty years ago 1,2 , how the vagus nerve detects inflammation to initiate the inflammatory reflex has remained unknown. Here we show that transient receptor potential ankyrin 1 (TRPA1) in sensory vagus neurons is required to sense interleukin-1β (IL-1β), a central cytokine mediator of inflammation and injury. Selective activation of vagus nerve TRPA1 using optopharmacology stimulated the inflammatory reflex to inhibit innate inflammatory responses to bacterial lipopolysaccharide and IL-1β. Proximity ligation assay and immunohistochemistry revealed that IL-1 receptors are coexpressed with TRPA1 in vagus sensory neurons. Whole-cell patch-clamp recordings reveal that TRPA1 is required to mediate IL-1β-dependent depolarization of vagus sensory neurons. Further, TRPA1-deficient mice lack inflammatory reflex attenuation of inflammation, fail to restrain cytokine release, and have significantly enhanced lethality to bacterial sepsis. Therefore, vagus neurons expressing TRPA1 are necessary and sufficient to activate the sensory arc of the inflammatory reflex to protect against harmful inflammation.Reflex neural circuits form the basis for physiological responses when the body is exposed to changing environmental and physiological conditions. The vagus nerve, originating in the brainstem medulla oblongata, is a paired structure that travels through the neck, thorax and abdomen to innervate visceral organs. In humans it is comprised of approximately 100,000 neurons; 80% are sensory, transmitting information to the brainstem in response to changes in the body's internal milieu to stimulate reflex motor signals that regulate heart rate, digestion, and other organ functions. The inflammatory reflex, a vagus circuit that inhibits inflammation to protect tissues from damage, stimulates anti-inflammatory T cells expressing choline acetyltransferase (T ChAT) in the spleen to produce acetylcholine which interacts with 7 nicotinic acetylcholine receptor (7nAChR)-expressing macrophages to inhibit release of TNF, IL-1, HMGB1 and other inflammatory cytokines 1-3 . Electronic stimulation of the inflammatory reflex confers significant protection in preclinical models of arthritis, inflammatory bowel disease, sepsis, and other syndromes, and significantly improves outcomes in clinical trials of rheumatoid arthritis and Crohn's disease 2,4,5 . Despite a detailed mechanistic understanding of signaling in the motor arc of the inflammatory reflex, the afferent arc mechanisms were previously unknown. TRPA1, a polymodal nociceptor cation channel expressed by unmyelinated peptidergic nociceptive C fiber neurons, is stimulated by reactive (hydrogen peroxide, formalin, acrolein) and non-rea...

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“…In agreement with our recent results 21,22 , administration of IL-1 to wild-type mice induces afferent vagus neuronal signal propagation ( Fig. 3a, 3c, and Supplemental Data Fig.…”

supporting

confidence: 93%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Transient Receptor Potential Ankyrin 1 Mediates Afferent Signals in the Inflammatory Reflex

Silverman

Gunasekaran

Chang

et al. 2019

Preprint

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“…For example, lumbar and vagal sensory neurons express IL-1 and TNF receptors. IL-1b and TNF-a can thus cause hyperalgesia and neuropeptide release [171][172][173][174]. IL-1R/IL-1b induces Na V 1.8 phosphorylation, decreasing neuronal action potential firing threshold [175,176].…”

Section: Cytokinesmentioning

confidence: 99%

Profiling of how nociceptor neurons detect danger – new and old foes

et al. 2019

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The host evolves redundant mechanisms to preserve physiological processing and homeostasis. These functions range from sensing internal and external threats, creating a memory of the insult and generating reflexes, which aim to resolve inflammation. Impairment in such functioning leads to chronic inflammatory diseases. By interacting through a common language of ligands and receptors, the immune and sensory nervous systems work in concert to accomplish such protective functions. Whilst this bidirectional communication helps to protect from danger, it can contribute to disease pathophysiology. Thus, the somatosensory nervous system is anatomically positioned within primary and secondary lymphoid tissues and mucosa to modulate immunity directly. Upstream of this interplay, neurons detect danger, which prompts the release of neuropeptides initiating (i) defensive reflexes (ranging from withdrawal response to coughing) and (ii) chemotaxis, adhesion and local infiltration of immune cells. The resulting outcome of such neuro‐immune interplay is still ill‐defined, but consensual findings start to emerge and support neuropeptides not only as blockers of TH1‐mediated immunity but also as drivers of TH2 immune responses. However, the modalities detected by nociceptors revealed broader than mechanical pressure and temperature sensing and include signals as various as cytokines and pathogens to immunoglobulins and even microRNAs. Along these lines, we aggregated various dorsal root ganglion sensory neuron expression profiling datasets supporting such wide‐ranging sensing capabilities to help identifying new danger detection modalities of these cells. Thus, revealing unexpected aspects of nociceptor neuron biology might prompt the identification of novel drivers of immunity, means to resolve inflammation and strategies to safeguard homeostasis.

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“…There is also evidence that certain cancer patients have lowered levels of certain circulating cytokines that might benefit from immunotherapy to increase those levels (Khan et al, 2018). As techniques are developed to better understand the relationship between vagus nerve activity and cytokine signaling (Steinberg et al, 2016;Tsaava et al, 2019;Zanos et al, 2018), there may also be other physiological conditions that would benefit from intentionally increasing cytokine levels.…”

Section: Discussionmentioning

confidence: 99%

Serum cytokine levels are modulated by specific frequencies, amplitudes, and pulse widths of vagus nerve stimulation

Tsaava

Datta-Chaudhuri

et al. 2020

Preprint

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Electrical stimulation of peripheral nerves is a widely used technique to treat a variety of conditions including chronic pain, motor impairment, headaches, and epilepsy. Nerve stimulation to achieve efficacious symptomatic relief depends on the proper selection of electrical stimulation parameters to recruit the appropriate fibers within a nerve. Recently, electrical stimulation of the vagus nerve has shown promise for controlling inflammation and clinical trials have demonstrated efficacy for the treatment of inflammatory disorders. This application of vagus nerve stimulation activates the inflammatory reflex, reducing levels of inflammatory cytokines during inflammation.Here, we wanted to test whether altering the parameters of electrical vagus nerve stimulation would change circulating cytokine levels of normal healthy animals in the absence of increased inflammation. To examine this, we systematically tested a set of electrical stimulation parameters and measured serum cytokine levels in healthy mice. Surprisingly, we found that specific combinations of pulse width, pulse amplitude, and frequency produced significant increases of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα), while other parameters selectively lowered serum TNFα levels, as compared to sham-stimulated mice. In addition, serum levels of the anti-inflammatory cytokine interleukin-10 (IL-10) were significantly increased by select parameters of electrical stimulation but remained unchanged with others. These results indicate that electrical stimulation parameter selection is critically important for the modulation of cytokines via the cervical vagus nerve and that specific cytokines can be increased by electrical stimulation in the absence of inflammation. As the next generation of bioelectronic therapies and devices are developed to capitalize on the neural regulation of inflammation, the selection of nerve stimulation parameters will be a critically important variable for achieving cytokine-specific changes.

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Identification of cytokine-specific sensory neural signals by decoding murine vagus nerve activity

Cited by 160 publications

References 76 publications

Transient Receptor Potential Ankyrin 1 Mediates Afferent Signals in the Inflammatory Reflex

Transient Receptor Potential Ankyrin 1 Mediates Afferent Signals in the Inflammatory Reflex

Profiling of how nociceptor neurons detect danger – new and old foes

Serum cytokine levels are modulated by specific frequencies, amplitudes, and pulse widths of vagus nerve stimulation

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