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Sensory Neurons Innervate Peripheral Lymph Nodes and Locally Regulate Gene Expression in Postsynaptic Endothelium, Stromal Cells, and Innate Leukocytes

Siyi Huang, View ORCID ProfileCarly G. K. Ziegler, John Austin, Najat Mannoun, Marko Vukovic, Jose Ordovas-Montanes, Alex K. Shalek, Ulrich H. von Andrian
doi: https://doi.org/10.1101/833509
Siyi Huang
1The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
2Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA
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  • For correspondence: siyi_huang@hms.harvard.edu shalek@mit.edu uva@hms.harvard.edu
Carly G. K. Ziegler
1The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
3Institute for Medical Engineering & Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
4Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
5Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA 02139, USA
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  • ORCID record for Carly G. K. Ziegler
John Austin
1The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
2Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA
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Najat Mannoun
1The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
2Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA
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Marko Vukovic
1The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
3Institute for Medical Engineering & Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
4Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Jose Ordovas-Montanes
1The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
3Institute for Medical Engineering & Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
4Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
6Division of Gastroenterology, Boston Children’s Hospital, Boston, MA, 02115 USA
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Alex K. Shalek
1The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
2Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA
3Institute for Medical Engineering & Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
4Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
5Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA 02139, USA
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  • For correspondence: siyi_huang@hms.harvard.edu shalek@mit.edu uva@hms.harvard.edu
Ulrich H. von Andrian
1The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
2Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA
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  • For correspondence: siyi_huang@hms.harvard.edu shalek@mit.edu uva@hms.harvard.edu
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ABSTRACT

Immune responses within barrier tissues are regulated, in part, by nociceptors, specialized peripheral sensory neurons that detect noxious stimuli. Previous work has shown that nociceptor ablation not only alters local responses to immune challenge at peripheral sites, but also within draining lymph nodes (LNs). The mechanisms and significance of nociceptor-dependent modulation of LN function are unknown. Indeed, although sympathetic innervation of LNs is well documented, it has been unclear whether the LN parenchyma itself is innervated by sensory neurons. Here, using a combination of high-resolution imaging, retrograde viral tracing, single-cell transcriptomics (scRNA-seq), and optogenetics, we identified and functionally tested a sensory neuro-immune circuit that is preferentially located in the outermost cortex of skin-draining LNs. Transcriptomic profiling revealed that there are at least four discrete subsets of sensory neurons that innervate LNs with a predominance of peptidergic nociceptors, and an innervation pattern that is distinct from that in the surrounding skin. To uncover potential LN-resident communication partners for LN-innervating sensory neurons, we employed scRNA-seq to generate a draft atlas of all murine LN cells and, based on receptor-ligand expression patterns, nominated candidate target populations among stromal and immune cells. Using selective optogenetic stimulation of LN-innervating sensory axons, we directly experimentally tested our inferred connections. Acute neuronal activation triggered rapid transcriptional changes preferentially within our top-ranked putative interacting partners, principally endothelium and other nodal stroma cells, as well as several innate leukocyte populations. Thus, LNs are monitored by a unique population of sensory neurons that possesses immunomodulatory potential.

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Posted November 11, 2019.
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Sensory Neurons Innervate Peripheral Lymph Nodes and Locally Regulate Gene Expression in Postsynaptic Endothelium, Stromal Cells, and Innate Leukocytes
Siyi Huang, Carly G. K. Ziegler, John Austin, Najat Mannoun, Marko Vukovic, Jose Ordovas-Montanes, Alex K. Shalek, Ulrich H. von Andrian
bioRxiv 833509; doi: https://doi.org/10.1101/833509
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Sensory Neurons Innervate Peripheral Lymph Nodes and Locally Regulate Gene Expression in Postsynaptic Endothelium, Stromal Cells, and Innate Leukocytes
Siyi Huang, Carly G. K. Ziegler, John Austin, Najat Mannoun, Marko Vukovic, Jose Ordovas-Montanes, Alex K. Shalek, Ulrich H. von Andrian
bioRxiv 833509; doi: https://doi.org/10.1101/833509

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