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

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

The 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.

Original languageEnglish
Pages (from-to)1022-1036.e8
JournalImmunity
Volume54
Issue number5
DOIs
StatePublished - 11 May 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors

Funding

We thank O. Barak for “asking the right question,” helpful discussions and for commenting on the manuscript; I. Kahn for the optogenetics equipment; O. Izhar and A. Aronhiem for sharing mice; A. Monsonego for assisting with immunohistochemistry; and M. Schwartz, M. Rivlin, I. Goshen, D. Farfara and S. Berger for helpful discussions. We are grateful to J. Schiller, B. Maman, and S. Schwartz for their advice and help with the calcium imaging experiments and S. Berlin and R. Heinrich for their help with the clearing technique. We thank S. Schwarzbaum and U. Rolls for editing the manuscript and O. Shenker, A. Grau, E. Suss-Toby, M. Holdengreber and M. Gurewitz for technical support. We are grateful to the Adelis Foundation , the Allen and Jewel Prince Center for Neurodegenerative Processes of the Brain , and Colleck Research Fund for their support. This project has received funding from the European Commission Horizon 2020 research and innovation program under grant agreement no. 758952-ERC-2017-STG (NEIMO). A.R is an international Howard Hughes Medical Institute HHMI-Wellcome Trust scholar.

FundersFunder number
Allen and Jewel Prince Center for Neurodegenerative Processes of the Brain
European Commission Horizon 2020 research and innovation program758952-ERC-2017-STG
Achelis Foundation

    Keywords

    • MAdCAM-1
    • colitis
    • gut-brain axis
    • neuroimmunology
    • noradrenaline
    • optogenetics
    • sympathetic nervous system

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