Science

The Inflammatory Reflex

Inflammation plays a significant role in acute and chronic diseases including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), psoriasis, diabetes, heart disease, and multiple sclerosis.

SetPoint co-founder Kevin Tracey and his colleagues discovered and characterized the Inflammatory Reflex, which is a neurophysiological mechanism that regulates the body’s immune system. The Inflammatory Reflex senses infection, tissue injury and inflammation and relays this information to the central nervous system, which then reflexively increases neural signaling peripherally through the vagus nerve that extensively innervate the visceral organs. The signal is transmitted to a novel population of T cells in the spleen, which in turn direct effector cells including monocytes and macrophages to reduce their production of the mediators that initiate and perpetuate inflammation.

Dr. Tracey published his findings in Nature in May 2000. Since then, the Inflammatory Reflex has been characterized by his group and others in multiple peer-reviewed papers in leading scientific journals, exploring the potential of activating the Inflammatory Reflex to alleviate inflammation. Dr. Tracey co-founded SetPoint Medical with Dr. Shaw Warren to leverage these discoveries in developing new therapies to treat chronic inflammatory diseases.

Annotated Bibliography

Reviews

Andersson U, Tracey K. Reflex principles of immunological homeostasis. Ann Rev Immunol 2012; 30: 313. (http://www.ncbi.nlm.nih.gov/pubmed/22224768)
Review of the biology of the inflammatory reflex, and summary of studies showing improvement in several preclinical inflammation models after activation of the reflex 

Andersson U, Tracey KJ. Neural reflexes in inflammation and immunity. J Exp Med. 2012; 209:1057. (http://www.ncbi.nlm.nih.gov/pubmed/22665702)
Review focused on the immunologic and phylogenetic aspects of the inflammatory reflex 

Matteoli G, Boeckxstaens G. The vagal innervation of the gut and immune homeostasis. Gut 2013; 62:1214. (http://www.ncbi.nlm.nih.gov/pubmed/23023166)
Review of the role of the inflammatory reflex in the gut, and potential for treating inflammatory bowel disease and other GI inflammatory disorders

Olofsson P, et al. Rethinking inflammation: neural circuits in the regulation of immunity. Immunological Reviews 2012; 248(1):188. (http://www.ncbi.nlm.nih.gov/pubmed/22725962)
Review with focus on neuroanatomical and molecular mechanisms of the cholinergic anti-inflammatory pathway.

van Maanen MA, et al. The cholinergic anti-inflammatory pathway: Towards innovative treatment of rheumatoid arthritis. Nat Rev Rheumatol. 2009; 5:229 (http://www.ncbi.nlm.nih.gov/pubmed/19337288)
Review of evidence supporting the potential for activation of the inflammatory reflex to improve rheumatoid arthritis

Primary Literature

Borovikova L, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000; 405:458. (http://www.ncbi.nlm.nih.gov/pubmed/10839541)
First report to describe the inflammatory reflex and demonstrate the effect of electrical vagus nerve stimulation in reducing systemic inflammation

de Jonge W, et al. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nature Immunol 2005; 8:844. (http://www.ncbi.nlm.nih.gov/pubmed/16025117)
Electrical vagus nerve stimulation reduces trafficking of inflammatory cells to the intestine

Ghia J, et al. The vagus nerve: A tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology 2006; 131:1122. (http://www.ncbi.nlm.nih.gov/pubmed/17030182)
Vagotomy worsens and pharmacologic agonists improve disease severity in a standard murine model of colitis.

Huston JM, et al. Splenectomy inactivates the cholinergic anti-inflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med. 2006; 203:1623. (http://www.ncbi.nlm.nih.gov/pubmed/16785311)
An intact signaling pathway between the vagus nerve, splenic nerve and spleen is critical in mediating the effect of the inflammatory reflex in reducing inflammation in endotoxemia

Rosas-Ballina M, et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 2011; 334:98. (http://www.ncbi.nlm.nih.gov/pubmed/21921156)
Description of a novel splenic T cell population that mediates the inflammatory reflex by bridging signals between the splenic nerve and splenic macrophages

van Maanen M, et al. Stimulation of nicotinic acetylcholine receptors attenuates collagen-induced arthritis in mice. Arth Rheum 2009; 60:114. (http://www.ncbi.nlm.nih.gov/pubmed/19116908)
Pharmacologic activation of the inflammatory reflex reduces and vagotomy worsens disease severity in a standard rodent arthritis model

van Maanen M, et al. Role of the cholinergic nervous system in rheumatoid arthritis: Aggravation of arthritis in nicotinic acetylcholine receptor a7 subunit gene knockout mice. Ann Rheum Dis 2010; 69:1717. (http://www.ncbi.nlm.nih.gov/pubmed/20511609)
Blockade of the inflammatory reflex in nicotinic acetylcholine receptor a7 subunit gene knockout mice is associated with worsened disease in a murine arthritis model

Wang H, et al. Nicotinic acetylcholine receptor alpha 7 subunit is an essential regulator of inflammation. Nature. 2003; 421:384. (http://www.ncbi.nlm.nih.gov/pubmed/12508119)
First demonstration that the inflammatory reflex acts through the alpha 7 nicotinic acetylcholine receptor

Zhang Y, et al. Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model. Circ Heart Fail. 2009; 2:692. (http://www.ncbi.nlm.nih.gov/pubmed/19919995)
Demonstration of sustained reduction of systemic inflammatory markers in response to vagus nerve stimulation in a chronic congestive heart failure model

Sun P, et al. Involvement of MAPK/NF-κB signaling in the activation of the cholinergic anti-inflammatory pathway in experimental colitis by chronic vagus nerve stimulation. PLoS One 2013; 8:e69424. (http://www.ncbi.nlm.nih.gov/pubmed/23936328)
Efficacy of electrical vagus nerve stimulation is demonstrated in a standard rodent colitis model of inflammatory bowel disease.