Lymph nodes are innervated by a unique population of sensory neurons with immunomodulatory potential

Siyi Huang; Carly G K Ziegler; John Austin; Najat Mannoun; Marko Vukovic; Jose Ordovas-Montanes; Alex K Shalek; Ulrich H von Andrian

doi:10.1016/j.cell.2020.11.028

Lymph nodes are innervated by a unique population of sensory neurons with immunomodulatory potential

Cell. 2021 Jan 21;184(2):441-459.e25. doi: 10.1016/j.cell.2020.11.028. Epub 2020 Dec 16.

Authors

Siyi Huang¹, Carly G K Ziegler², John Austin³, Najat Mannoun³, Marko Vukovic⁴, Jose Ordovas-Montanes⁵, Alex K Shalek⁶, Ulrich H von Andrian⁷

Affiliations

¹ The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA. Electronic address: siyi_huang@hms.harvard.edu.
² The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Institute for Medical Engineering & Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA 02139, USA; Harvard Graduate Program in Biophysics, Harvard University, Boston, MA 02115, USA.
³ The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA.
⁴ The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Institute for Medical Engineering & Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Institute for Medical Engineering & Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Gastroenterology, Boston Children's Hospital, Boston, MA 02115, USA.
⁶ The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA; Institute for Medical Engineering & Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Cambridge, MA 02139, USA. Electronic address: shalek@mit.edu.
⁷ The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA. Electronic address: uva@hms.harvard.edu.

Abstract

Barrier tissue immune responses are regulated in part by nociceptors. Nociceptor ablation alters local immune responses at peripheral sites and within draining lymph nodes (LNs). The mechanisms and significance of nociceptor-dependent modulation of LN function are unknown. Using high-resolution imaging, viral tracing, single-cell transcriptomics, and optogenetics, we identified and functionally tested a sensory neuro-immune circuit that is responsive to lymph-borne inflammatory signals. Transcriptomics profiling revealed that multiple sensory neuron subsets, predominantly peptidergic nociceptors, innervate LNs, distinct from those innervating surrounding skin. To uncover LN-resident cells that may interact with LN-innervating sensory neurons, we generated a LN single-cell transcriptomics atlas and nominated nociceptor target populations and interaction modalities. Optogenetic stimulation of LN-innervating sensory fibers triggered rapid transcriptional changes in the predicted interacting cell types, particularly endothelium, stromal cells, and innate leukocytes. Thus, a unique population of sensory neurons monitors peripheral LNs and may locally regulate gene expression.

Keywords: lymph node; neuro-immunology; nociceptor; optogenetics; sensory neuron; single-cell RNA-seq.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials
Animals
Immunomodulation*
Inflammation / pathology
Lymph Nodes / immunology*
Lymph Nodes / innervation*
Mice
Nociceptors / metabolism
Optogenetics
Peptides / metabolism
Sensory Receptor Cells / immunology*
Skin / innervation
Sympathetic Nervous System / physiology
Toll-Like Receptors / agonists
Toll-Like Receptors / metabolism

Substances

Peptides
Toll-Like Receptors

Abstract

Publication types

MeSH terms

Substances

Grants and funding