Identification of a brainstem locus that inhibits tumor necrosis factor

Kressel, A. M., Tsaava, T., Levine, Y. A., Chang, E. H., Addorisio, M. E., Chang, Q., Burbach, B. J., Carnevale, D., Lembo, G., Zador, A. M., Andersson, U., Pavlov, V. A., Chavan, S. S., Tracey, K. J. (November 2020) Identification of a brainstem locus that inhibits tumor necrosis factor. Proc Natl Acad Sci U S A, 117 (47). pp. 29803-29810. ISSN 0027-8424 (Print)0027-8424

DOI: 10.1073/pnas.2008213117


In the brain, compact clusters of neuron cell bodies, termed nuclei, are essential for maintaining parameters of host physiology within a narrow range optimal for health. Neurons residing in the brainstem dorsal motor nucleus (DMN) project in the vagus nerve to communicate with the lungs, liver, gastrointestinal tract, and other organs. Vagus nerve-mediated reflexes also control immune system responses to infection and injury by inhibiting the production of tumor necrosis factor (TNF) and other cytokines in the spleen, although the function of DMN neurons in regulating TNF release is not known. Here, optogenetics and functional mapping reveal cholinergic neurons in the DMN, which project to the celiac-superior mesenteric ganglia, significantly increase splenic nerve activity and inhibit TNF production. Efferent vagus nerve fibers terminating in the celiac-superior mesenteric ganglia form varicose-like structures surrounding individual nerve cell bodies innervating the spleen. Selective optogenetic activation of DMN cholinergic neurons or electrical activation of the cervical vagus nerve evokes action potentials in the splenic nerve. Pharmacological blockade and surgical transection of the vagus nerve inhibit vagus nerve-evoked splenic nerve responses. These results indicate that cholinergic neurons residing in the brainstem DMN control TNF production, revealing a role for brainstem coordination of immunity.

Item Type: Paper
Additional Information: 1091-6490 Kressel, Adam M Orcid: 0000-0003-1082-5877 Tsaava, Tea Levine, Yaakov A Orcid: 0000-0002-3313-6858 Chang, Eric H Orcid: 0000-0001-5592-4276 Addorisio, Meghan E Chang, Qing Burbach, Barry J Carnevale, Daniela Orcid: 0000-0002-5016-3161 Lembo, Giuseppe Orcid: 0000-0002-3510-223x Zador, Anthony M Andersson, Ulf Orcid: 0000-0003-0316-3860 Pavlov, Valentin A Orcid: 0000-0002-1994-2853 Chavan, Sangeeta S Orcid: 0000-0002-4822-3356 Tracey, Kevin J P01 AI102852/AI/NIAID NIH HHS/United States R01 GM132672/GM/NIGMS NIH HHS/United States R35 GM118182/GM/NIGMS NIH HHS/United States R01 GM128008/GM/NIGMS NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Proc Natl Acad Sci U S A. 2020 Nov 24;117(47):29803-29810. doi: 10.1073/pnas.2008213117. Epub 2020 Nov 9.
Uncontrolled Keywords: *tnf *cytokines *dorsal motor nucleus *inflammatory reflex *vagus nerve application relevant to this work and have assigned their rights to the Feinstein Institutes for Medical Research. Y.A.L. is an employee of SetPoint Medical.
CSHL Authors:
Communities: CSHL labs > Zador lab
Depositing User: Matthew Dunn
Date: 24 November 2020
Date Deposited: 19 Feb 2021 20:06
Last Modified: 19 Feb 2021 20:06
PMCID: PMC7703602

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