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

Sokal, DM; McSloy, A; Donega, M; Kirk, J; Colas, RA; Dolezalova, N; Gomez, EA; Gupta, I; Fjordbakk, CT; Ouchouche, S; Matteucci, PB; Schlegel, K; Bashirullah, R; Werling, D; Harman, K; Rowles, A; Yazicioglu, RF; Dalli, J; Chew, DJ; Perkins, JD

doi:10.3389/fimmu.2021.649786

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

Sokal, DM; McSloy, A; Donega, M; Kirk, J; Colas, RA; Dolezalova, N; Gomez, EA; Gupta, I; Fjordbakk, CT; Ouchouche, S; Matteucci, PB; Schlegel, K; Bashirullah, R; Werling, D; Harman, K; Rowles, A; Yazicioglu, RF; Dalli, J; Chew, DJ; Perkins, JD

Authors

DM Sokal

A McSloy

M Donega

J Kirk

RA Colas

N Dolezalova

EA Gomez

I Gupta

CT Fjordbakk

S Ouchouche

PB Matteucci

K Schlegel

R Bashirullah

D Werling

K Harman

A Rowles

RF Yazicioglu

J Dalli

DJ Chew

JD Perkins

Abstract

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.

Citation

Sokal, D., McSloy, A., Donega, M., Kirk, J., Colas, R., Dolezalova, N., …Perkins, J. (2021). Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs. Frontiers in Immunology, 12, https://doi.org/10.3389/fimmu.2021.649786

Journal Article Type	Article
Acceptance Date	Mar 28, 2021
Publication Date	2021
Deposit Date	Dec 23, 2021
Publicly Available Date	Dec 23, 2021
Publisher	Frontiers Media
Peer Reviewed	Peer Reviewed
Volume	12
DOI	https://doi.org/10.3389/fimmu.2021.649786
Keywords	autonomic nervous system; neuromodulation; stimulation; endotoxemia; specialized pro resolving mediators; inflammation; bioelectronic medicine; splenic nerve
Public URL	https://rvc-repository.worktribe.com/output/1554082