Optogenetic activation of local colonic sympathetic innervations attenuates colitis by limiting immune cell extravasation

Maya Schiller,Hilla Azulay-Debby,Nadia Boshnak,Yehezqel Elyahu,Ben Korin,Tamar L Ben-Shaanan,Tamar Koren,Maria Krot,Fahed Hakim,Asya Rolls

doi:10.1016/j.immuni.2021.04.007

Abstract

SummaryThe sympathetic nervous system is composed of an endocrine arm, regulating blood adrenaline and noradrenaline, and a local arm, a network of fibers innervating immune organs. Here, we investigated the impact of the local arm of the SNS in an inflammatory response in the colon. Intra-rectal insertion of an optogenetic probe in mice engineered to express channelrhodopsin-2 in tyrosine hydroxylase cells activated colonic sympathetic fibers. In contrast to systemic application of noradrenaline, local activation of sympathetic fibers attenuated experimental colitis and reduced immune cell abundance. Gene expression profiling showed decreased endothelial expression of the adhesion molecule MAdCAM-1 upon optogenetic stimulation; this decrease was sensitive to adrenergic blockers and 6-hydroxydopamine. Antibody blockade of MAdCAM-1 abrogated the optogenetic effect on immune cell extravasation into the colon and the pathology. Thus, sympathetic fibers control colonic inflammation by regulating immune cell extravasation from circulation, a mechanism likely relevant in multiple organs.

Highlights

As a central regulator of homeostasis, the brain receives multiple layers of information from the body, including feedback regarding metabolism, temperature, inflammation and tissue damage
Optogenetics activate local sympathetic fibers in the colon To characterize the effects of local sympathetic innervations on gastrointestinal tract (GIT) immunity, we focused on the colon
tyrosine hydroxylase (TH) is an enzyme required for catecholamine synthesis (Kuhar et al, 1999), thereby targeting ChR2 expression to sympathetic neurons, which allows their selective activation

Summary

Introduction

As a central regulator of homeostasis, the brain receives multiple layers of information from the body, including feedback regarding metabolism, temperature, inflammation and tissue damage The brain integrates this information to orchestrate behavioral and physiological functions, including the activity of the organism’s main protective mechanism, the immune system (Ben-Shaanan et al, 2018; Elenkov et al, 2000; Sloan et al, 2007; Takahashi et al, 2018). Stroke suppresses inflammation via hepatic invariant natural killer T (iNKT) cells (Wong et al, 2011) These diverse effects of the brain on immunity can be mediated by hormonal mediators (e.g., cortisol; Morey et al, 2015), or peripheral innervations, via the parasympathetic nervous system (PSNS) and the sympathetic nervous systems (SNS). We focus on the SNS as a key pathway relaying information from the brain to the immune system (Elenkov et al, 2000; Nance and Sanders, 2007)

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