Kevin J Tracey

Feinstein Institute for Medical Research · Laboratory of Biomedical Science

Background Acute liver injury (ALI) that progresses into acute liver failure (ALF) is a life-threatening condition with an increasing incidence and associated costs. Acetaminophen (N-acetyl-p-aminophenol, APAP) overdosing is among the leading causes of ALI and ALF in the Northern Hemisphere. Brain dysfunction defined as hepatic encephalopathy is on...

Multiple sclerosis (MS) is a demyelinating central nervous system (CNS) disorder that is associated with functional impairment and accruing disability. There are multiple U.S. Food and Drug Administration (FDA)-approved drugs that effectively dampen inflammation and slow disability progression. However, these agents do not work well for all patient...

Background Key to the advancement of the field of bioelectronic medicine is the identification of novel pathways of neural regulation of immune function. Sensory neurons (termed nociceptors) recognize harmful stimuli and initiate a protective response by eliciting pain and defensive behavior. Nociceptors also interact with immune cells to regulate...

The nervous system has an important role in the regulation of cytokines and inflammation ( Nature, 2002). The celiac-superior mesenteric ganglion complex (CSMGC) is an important component of the vagus nerve based inflammatory reflex, which controls inflammation ( Nat Neuroscience 2017). In addition to receiving cholinergic innervations from the eff...

The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. Recently, using optogenetics it has been demonstrated that the brainstem’s dorsal motor nucleus of the vagus (DMN) is a significant source of efferent vagus nerve fibers that control inflammation. In contrast to optogenetics, electrical neuron...

The innate fear odorant 2-Methylthiazoline (2-MT) elicits highly robust innate fear and defensive behaviors, such as freezing, hypothermia and bradycardia via activation of transient receptor potential ankyrin 1 (TRPA1) channels. Activation of TRPA1-expressing vagus nerve fibers also regulates IL-1β induced hypothermia and reflex anti-inflammatory...

The immune and nervous systems are intricately linked. However, mechanistic pathways linking cytokine-mediated stress networks in the brain to peripheral immune and cardiac functions remain poorly understood. Here, we identify a specific population of neurons in the bed nucleus of the stria terminalis (BNST), which shape diverse responses to interl...

The field of cancer neuroscience has begun to define the contributions of nerves to cancer initiation and progression; here, we highlight the future directions of basic and translational cancer neuroscience for malignancies arising outside of the central nervous system.

The pathogenic mechanisms of bacterial infections and resultant sepsis are partly attributed to dysregulated inflammatory responses sustained by some late-acting mediators including the procathepsin-L (pCTS-L). It was entirely unknown whether any compounds of the U.S. Drug Collection could suppress pCTS-L-induced inflammation, and pharmacologically...

Pancreatic ductal adenocarcinoma (PDAC) poses a formidable challenge to public health, with a dismal 5-year survival rate and a projected rise as the second leading cause of cancer-related deaths by 2030. The pathogenesis of PDAC involves a robust desmoplastic reaction and a complex tumor microenvironment (TME), constituting up to 80% of the tumor...

Autonomic dysfunction is a clinical hallmark of infection caused by SARS‐CoV‐2, but the underlying mechanisms are unknown. The vagus nerve inflammatory reflex is an important, well‐characterized mechanism for the reflexive suppression of cytokine storm, and its experimental or clinical impairment facilitates the onset and progression of hyperinflam...

Background Choline acetyltransferase (ChAT) is required for the biosynthesis of acetylcholine, the molecular mediator that inhibits cytokine production in the cholinergic anti‐inflammatory pathway of the vagus nerve inflammatory reflex. Abundant work has established the biology of cytoplasmic ChAT in neurons, but much less is known about the potent...

Background Acute pancreatitis is a common and serious inflammatory condition currently lacking disease modifying therapy. The cholinergic anti-inflammatory pathway (CAP) is a potent protective anti-inflammatory response activated by vagus nerve-dependent α7 nicotinic acetylcholine receptor (α7nAChR) signaling using splenic CD4 ⁺ T cells as an inter...

The emerging field of bioelectronic medicine (BEM) is poised to make a significant impact on the treatment of several neurological and inflammatory disorders. With several BEM therapies being recently approved for clinical use and others in late-phase clinical trials, the 2022 BEM summit was a timely scientific meeting convening a wide range of exp...

Background and aims: Crohn's disease (CD) is a debilitating inflammatory condition affecting the gastrointestinal tract. There is no cure and sustained clinical and endoscopic remission is achieved by fewer than half of patients with current therapies. The immunoregulatory function of the vagus nerve, the "inflammatory reflex", has been establishe...

Chronic low-grade inflammation has been recognized as an underlying event linking obesity to cardiovascular disease (CVD). However, inflammatory alterations in individuals who are overweight remain understudied. To provide insight, we determined the levels of key circulating biomarkers of endotoxemia and inflammation, including lipopolysaccharide-b...

Deficiency of coagulation factor VIII in hemophilia A disrupts clotting and prolongs bleeding. While the current mainstay of therapy is infusion of factor VIII concentrates, inhibitor antibodies often render these ineffective. Because preclinical evidence shows electrical vagus nerve stimulation accelerates clotting to reduce hemorrhage without pre...

Chronic low-grade inflammation has been recognized as an underlying event linking obesity to cardiovascular disease (CVD). However, inflammatory alterations in individuals who are overweight remain understudied. To provide insight, we determined the levels of key circulating biomarkers of endotoxemia and inflammation, including lipopolysaccharide-b...

Background The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute to the regulation of inflammation is the brainstem dorsal motor nucleus of the vagus (DMN) as recently shown using optogenetics. In contrast to optogenetics, electrical n...

The pathogenesis of microbial infections and sepsis is partly attributable to dysregulated innate immune responses propagated by late-acting proinflammatory mediators such as procathepsin L (pCTS-L). It was previously not known whether any natural product could inhibit pCTS-L-mediated inflammation or could be strategically developed into a potentia...

The brain maintains a homeostatic condition in the body through neuronal communication with peripheral organs. The immune system is also regulated by the nervous system with principles of reflex regulation. Neuronal pathways, including the vagus nerve-based inflammatory reflex, are physiological regulators of immune function and inflammation. Howev...

Introduction Inflammation is an inherently self-amplifying process, resulting in progressive tissue damage when unresolved. A brake on this positive feedback system is provided by the nervous system which has evolved to detect inflammatory signals and respond by activating anti-inflammatory processes, including the cholinergic anti-inflammatory pat...

Focused ultrasound stimulation (FUS) activates mechanosensitive ion channels and is emerging as a method of noninvasive neuromodulation. In preclinical studies, FUS of the spleen (sFUS) activates an anti-inflammatory neural pathway which suppresses acute and chronic inflammation. However, the relevance of sFUS for regulating inflammatory responses...

Background: There is emerging evidence that the nervous system regulates immune and metabolic alterations mediating Metabolic syndrome (MetS) pathogenesis via the vagus nerve. This study evaluated the effects of transcutaneous auricular vagus nerve stimulation (TAVNS) on key cardiovascular and inflammatory components of MetS. Methods: We conduct...

Objective.Sensory nerves of the peripheral nervous system (PNS) transmit afferent signals from the body to the brain. These peripheral nerves are composed of distinct subsets of fibers and associated cell bodies, which reside in peripheral ganglia distributed throughout the viscera and along the spinal cord. The vagus nerve (cranial nerve X) is a c...

Background: There is emerging evidence that the nervous system regulates immune and metabolic alterations mediating Metabolic syndrome (MetS) pathogenesis via the vagus nerve. This study evaluated the effects of transcutaneous auricular vagus nerve stimulation (TAVNS) on key cardiovascular and inflammatory components of MetS. Methods: We conducted...

Antibody-based strategies have been attempted to antagonize early cytokines of sepsis, but not yet been tried to target inducible late-acting mediators. Here, we report that the expression and secretion of procathepsin-L (pCTS-L) was induced by serum amyloid A (SAA) in innate immune cells, contributing to its late and systemic accumulation in exper...

Vagal fibers travel inside fascicles and form branches to innervate organs and regulate organ functions. Existing vagus nerve stimulation (VNS) therapies activate vagal fibers non-selectively, often resulting in reduced efficacy and side effects from non-targeted organs. The transverse and longitudinal arrangement of fibers inside the vagal trunk w...

Background Inflammation, the physiological response to infection and injury, is coordinated by the immune and nervous systems. Interleukin-1β (IL-1β) and other cytokines produced during inflammatory responses activate sensory neurons (nociceptors) to mediate the onset of pain, sickness behavior, and metabolic responses. Although nociceptors express...

Background Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19....

Background Vagus nerve stimulation (VNS) has shown therapeutic potential in a variety of different diseases with many ongoing clinical trials. The role of VNS in reducing ischemic injury in the brain requires further evaluation. Cardiac arrest (CA) causes global ischemia and leads to the injury of vital organs, especially the brain. In this study,...

Background: Brain metabolic alterations and neuroinflammation have been reported in several peripheral inflammatory conditions and present significant potential for targeting with new diagnostic approaches and treatments. However, non-invasive evaluation of these alterations remains a challenge. Methods: Here, we studied the utility of a micro p...

Peptides, polymers of amino acids, comprise a vital and expanding therapeutic approach. Their rapid degradation by proteases, however, represents a major limitation to their therapeutic utility and chemical modifications to native peptides have been employed to mitigate this weakness. Herein, we describe functionalized thiocarbazate scaffolds as pr...

Background: Myelodysplastic syndrome (MDS) is associated with persistent immune activation. High mobility group box-1 (HMGB1) is a ubiquitous, functionally diverse, non-histone intranuclear protein. During acute and chronic inflammatory states, HMGB1 is actively released by inflammatory cells, further amplifying the inflammatory response. A role i...

Background Neuroinflammation is an important driver of acute and chronic pain states. Therefore, targeting molecular mediators of neuroinflammation may present an opportunity for developing novel pain therapies. In preclinical models of neuroinflammatory pain, calcitonin gene-related peptide (CGRP), substance P and high mobility group box 1 protein...

Background: Vagal reflexes regulate homeostasis in visceral organs and systems through afferent and efferent neurons and nerve fibers. Small, unmyelinated, C-type afferents comprise over 80% of fibers in the vagus and form the sensory arc of autonomic reflexes of the gut, lungs, heart and vessels and the immune system. Selective bioelectronic acti...

The nervous system maintains homeostasis and health. Homeostatic disruptions underlying the pathobiology of many diseases can be controlled by bioelectronic devices targeting CNS and peripheral neural circuits. New insights into the regulatory functions of the nervous system and technological developments in bioelectronics drive progress in the eme...

The cholinergic anti-inflammatory pathway is the efferent arm of the inflammatory reflex, a neural circuit through which the CNS can modulate peripheral immune responses. Signals communicated via the vagus and splenic nerves use acetylcholine, produced by Choline acetyltransferase (ChAT)+ T cells, to downregulate the inflammatory actions of macroph...

Peripheral neurons that sense glucose relay signals of glucose availability to integrative clusters of neurons in the brain. However, the roles of such signalling pathways in the maintenance of glucose homoeostasis and their contribution to disease are unknown. Here we show that the selective activation of the nerve plexus of the hepatic portal sys...

The peripheral nervous system communicates with the immune system in response to injury or infection. In the case of inflammation, sensory signals travel up to the brain via the vagus nerve, which is a major pathway for neuro‐immune communication. While previous work from our group showed that cytokines administered systemically were associated wit...

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, affects up to 3 million people in the United States alone, significantly worsens a patient's quality of life, and is associated with a high financial burden. Current treatments for IBD are mainly biologicals that have significant side effects. No efficient pharmacol...

Background: The COVID-19 pandemic in the U.S. caused > 48 million infections and >500,000 deaths. Famotidine, a histamine H2 receptor antagonist widely used to treat acid reflux and gastritis, is associated with improved survival and attenuated COVID-19 disease severity (Mather JF et al. Am J Gastroenterol. 115:1617,2020; Freedberg DE, et al. Gast...

The vagus nerve plays a key role in the regulation of inflammation within the inflammatory reflex (Annu Rev Immunol, 2018, 36:783). In this major physiological neuroimmunoregulatory mechanism, efferent vagus nerve cholinergic axons interact with catecholaminergic neurons of the splenic nerve in the celiac-superior mesenteric ganglion (CSMG) complex...

Acute respiratory distress syndrome (ARDS) is a life-threatening form of acute lung injury and respiratory failure. The pandemic of SARS-CoV-2 has resulted in over 5 million deaths worldwide and many of those deaths have been attributed to complications associated with ARDS. No efficient pharmacological treatments for ARDS are currently available....

The inflammatory reflex is a vagus nerve-mediated and brainstem-integrated physiological mechanism that regulates immunity and inflammation (Annu Rev Immunol, 2018, 36:783). The efferent vagus nerve originates in brainstem nuclei, including the dorsal motor nucleus of the vagus (DMN). Recently, it was shown that optogenetic stimulation of cholinerg...

Objective Systemic inflammatory conditions are finely controlled not only by the immune system but also by the neuronal system in the body. While the vagus nerve is the key neuronal pathway to control the peripheral immune system, known as the inflammatory reflex, it is largely unknown how the brain regulates the reflex. The purpose of this study i...

Cytokines are secreted signaling proteins that are important mediators of inflammation. While prior work has demonstrated that the level of cytokines can be regulated by nerve stimulation, the role of the nervous system in sensing these immune mediators is still poorly understood. During periods of inflammation, it has been shown that sensory signa...

TRPA1 is a non-specific cation channel, that has been previously implicated in temperature regulation and inflammation. Administration of TRPA1 agonists induce significant changes in body temperature. Similarly, IL-1β, a cytokine mediator of inflammation and injury, induces a significant change in body temperature. Here we reasoned that TRPA1 plays...

Excessive immune cell activation and cytokine release leading to inflammatory conditions are associated with bidirectional immune system-brain communication and other physiological responses. The vagus nerve conveys sensory information to the brain and brain derived immunoregulatory signals suppressing peripheral cytokine levels and inflammation. A...

Chronic pain affects the daily lives of millions of Americans and presents an economic burden of $600 Billion per year. Opiods and other pharmaceutical approaches for the management of chronic pain have notorious detremental side effects. Thus, there is a need for understanding of pain for better therapeutics. Neuroinflammation is closely associate...

Background. Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease , attenuates the clinical course of COVID-19...

Afferent and efferent fibers in the vagus travel inside nerve fascicles and form branches to innervate organs and regulate organ functions. The organization of fibers and fascicles in the vagus trunk, with respect to the functions they mediate and the organs they innervate, remains largely unknown. Accordingly, it is unknown whether that anatomical...

Objective We assessed whether famotidine improved inflammation and symptomatic recovery in outpatients with mild to moderate COVID-19. Design Randomised, double-blind, placebo-controlled, fully remote, phase 2 clinical trial ( NCT04724720 ) enrolling symptomatic unvaccinated adult outpatients with confirmed COVID-19 between January 2021 and April...

Purpose of review: To describe features and implications of chronic systemic inflammation in individuals with spinal cord injury (SCI) and to summarize the growing therapeutic possibilities to explore the vagus nerve-mediated inflammatory reflex in this context. Recent findings: The discovery of the inflammatory reflex provides a rationale to ex...

Anemia of inflammation, also known as anemia of chronic disease, is refractory to erythropoietin (EPO) treatment, but the mechanisms underlying the EPO-refractory state are unclear. Here, we demonstrate that high mobility group box-1 protein (HMGB1), a damage-associated molecular pattern molecule recently implicated in anemia development during sep...

Background Hepatic ischemia and reperfusion (I/R) injury is commonly associated with surgical liver resection or transplantation, and represents a major cause of liver damage and graft failure. Currently, there are no effective therapies to prevent hepatic I/R injury other than ischemic preconditioning and some preventative strategies. Previously,...

A SARS-like coronavirus 2 (SARS-CoV-2) has caused a pandemic Coronavirus Disease 2019 (COVID-19) that killed more than 3.3 million people worldwide. Like the SARS-CoV, SARS-CoV-2 also employs a receptor-binding motif (RBM) of its spike protein to bind a host receptor, the angiotensin-converting enzyme 2 (ACE2), to gain entry. Currently, several mRN...

Background High mobility group box 1 (HMGB1) is a nuclear protein with extracellular inflammatory cytokine activity. It is passively released during cell death and secreted by activated cells of many lineages. HMGB1 contains three conserved redox-sensitive cysteine residues: cysteines in position 23 and 45 (C23 and C45) can form an intramolecular d...

Acetylcholine (ACh) decreases blood pressure by stimulating endothelium nitric oxide-dependent vasodilation in resistance arterioles. Normal plasma contains choline acetyltransferase (ChAT) and its biosynthetic product ACh at appreciable concentrations to potentially act upon the endothelium to affect blood pressure. Recently we discovered a T-cell...

BACKGROUND Current inflammatory bowel disease (IBD) therapies are limited by incomplete efficacy, loss of response, side effects and high costs. Vagal nerve stimulation (VNS) is an investigational Bioelectronic Medicine therapy targeting the nervous system to treat IBD through an ‘inflammatory reflex’ that reduces systemic inflammation. Data in hum...

Novel research in the field of bioelectronic medicine requires neuromodulation systems that pair high-performance neurostimulation and bio-signal acquisition hardware with advanced signal processing and control algorithms. Although mice are the most commonly used animal in medical research, the size, weight, and power requirements of such neuromodu...