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Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs

Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. We recently demonstrated that stimulation of near-organ autonomic nerves to the spleen can be harnessed to modulate the inflammatory response in an anesthetized pig mo...

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Autores principales: Sokal, David M., McSloy, Alex, Donegà, Matteo, Kirk, Joseph, Colas, Romain A., Dolezalova, Nikola, Gomez, Esteban A., Gupta, Isha, Fjordbakk, Cathrine T., Ouchouche, Sebastien, Matteucci, Paul B., Schlegel, Kristina, Bashirullah, Rizwan, Werling, Dirk, Harman, Kim, Rowles, Alison, Yazicioglu, Refet Firat, Dalli, Jesmond, Chew, Daniel J., Perkins, Justin D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043071/
https://www.ncbi.nlm.nih.gov/pubmed/33859641
http://dx.doi.org/10.3389/fimmu.2021.649786
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author Sokal, David M.
McSloy, Alex
Donegà, Matteo
Kirk, Joseph
Colas, Romain A.
Dolezalova, Nikola
Gomez, Esteban A.
Gupta, Isha
Fjordbakk, Cathrine T.
Ouchouche, Sebastien
Matteucci, Paul B.
Schlegel, Kristina
Bashirullah, Rizwan
Werling, Dirk
Harman, Kim
Rowles, Alison
Yazicioglu, Refet Firat
Dalli, Jesmond
Chew, Daniel J.
Perkins, Justin D.
author_facet Sokal, David M.
McSloy, Alex
Donegà, Matteo
Kirk, Joseph
Colas, Romain A.
Dolezalova, Nikola
Gomez, Esteban A.
Gupta, Isha
Fjordbakk, Cathrine T.
Ouchouche, Sebastien
Matteucci, Paul B.
Schlegel, Kristina
Bashirullah, Rizwan
Werling, Dirk
Harman, Kim
Rowles, Alison
Yazicioglu, Refet Firat
Dalli, Jesmond
Chew, Daniel J.
Perkins, Justin D.
author_sort Sokal, David M.
collection PubMed
description Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. We recently demonstrated that stimulation of near-organ autonomic nerves to the spleen can be harnessed to modulate the inflammatory response in an anesthetized pig model. The development of neuromodulation therapy for the clinic requires chronic efficacy and safety testing in a large animal model. This manuscript describes the effects of longitudinal conscious splenic nerve neuromodulation in chronically-implanted pigs. Firstly, clinically-relevant stimulation parameters were refined to efficiently activate the splenic nerve while reducing changes in cardiovascular parameters. Subsequently, pigs were implanted with a circumferential cuff electrode around the splenic neurovascular bundle connected to an implantable pulse generator, using a minimally-invasive laparoscopic procedure. Tolerability of stimulation was demonstrated in freely-behaving pigs using the refined stimulation parameters. Longitudinal stimulation significantly reduced circulating tumor necrosis factor alpha levels induced by systemic endotoxemia. This effect was accompanied by reduced peripheral monocytopenia as well as a lower systemic accumulation of CD16(+)CD14(high) pro-inflammatory monocytes. Further, lipid mediator profiling analysis demonstrated an increased concentration of specialized pro-resolving mediators in peripheral plasma of stimulated animals, with a concomitant reduction of pro-inflammatory eicosanoids including prostaglandins. Terminal electrophysiological and physiological measurements and histopathological assessment demonstrated integrity of the splenic nerves up to 70 days post implantation. These chronic translational experiments demonstrate that daily splenic nerve neuromodulation, via implanted electronics and clinically-relevant stimulation parameters, is well tolerated and is able to prime the immune system toward a less inflammatory, pro-resolving phenotype.
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spelling pubmed-80430712021-04-14 Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs Sokal, David M. McSloy, Alex Donegà, Matteo Kirk, Joseph Colas, Romain A. Dolezalova, Nikola Gomez, Esteban A. Gupta, Isha Fjordbakk, Cathrine T. Ouchouche, Sebastien Matteucci, Paul B. Schlegel, Kristina Bashirullah, Rizwan Werling, Dirk Harman, Kim Rowles, Alison Yazicioglu, Refet Firat Dalli, Jesmond Chew, Daniel J. Perkins, Justin D. Front Immunol Immunology Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. We recently demonstrated that stimulation of near-organ autonomic nerves to the spleen can be harnessed to modulate the inflammatory response in an anesthetized pig model. The development of neuromodulation therapy for the clinic requires chronic efficacy and safety testing in a large animal model. This manuscript describes the effects of longitudinal conscious splenic nerve neuromodulation in chronically-implanted pigs. Firstly, clinically-relevant stimulation parameters were refined to efficiently activate the splenic nerve while reducing changes in cardiovascular parameters. Subsequently, pigs were implanted with a circumferential cuff electrode around the splenic neurovascular bundle connected to an implantable pulse generator, using a minimally-invasive laparoscopic procedure. Tolerability of stimulation was demonstrated in freely-behaving pigs using the refined stimulation parameters. Longitudinal stimulation significantly reduced circulating tumor necrosis factor alpha levels induced by systemic endotoxemia. This effect was accompanied by reduced peripheral monocytopenia as well as a lower systemic accumulation of CD16(+)CD14(high) pro-inflammatory monocytes. Further, lipid mediator profiling analysis demonstrated an increased concentration of specialized pro-resolving mediators in peripheral plasma of stimulated animals, with a concomitant reduction of pro-inflammatory eicosanoids including prostaglandins. Terminal electrophysiological and physiological measurements and histopathological assessment demonstrated integrity of the splenic nerves up to 70 days post implantation. These chronic translational experiments demonstrate that daily splenic nerve neuromodulation, via implanted electronics and clinically-relevant stimulation parameters, is well tolerated and is able to prime the immune system toward a less inflammatory, pro-resolving phenotype. Frontiers Media S.A. 2021-03-29 /pmc/articles/PMC8043071/ /pubmed/33859641 http://dx.doi.org/10.3389/fimmu.2021.649786 Text en Copyright © 2021 Sokal, McSloy, Donegà, Kirk, Colas, Dolezalova, Gomez, Gupta, Fjordbakk, Ouchouche, Matteucci, Schlegel, Bashirullah, Werling, Harman, Rowles, Yazicioglu, Dalli, Chew and Perkins https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Sokal, David M.
McSloy, Alex
Donegà, Matteo
Kirk, Joseph
Colas, Romain A.
Dolezalova, Nikola
Gomez, Esteban A.
Gupta, Isha
Fjordbakk, Cathrine T.
Ouchouche, Sebastien
Matteucci, Paul B.
Schlegel, Kristina
Bashirullah, Rizwan
Werling, Dirk
Harman, Kim
Rowles, Alison
Yazicioglu, Refet Firat
Dalli, Jesmond
Chew, Daniel J.
Perkins, Justin D.
Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs
title Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs
title_full Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs
title_fullStr Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs
title_full_unstemmed Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs
title_short Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs
title_sort splenic nerve neuromodulation reduces inflammation and promotes resolution in chronically implanted pigs
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043071/
https://www.ncbi.nlm.nih.gov/pubmed/33859641
http://dx.doi.org/10.3389/fimmu.2021.649786
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