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

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 imag...

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Published in:	Cell Vol. 184; no. 2; pp. 441 - 459.e25
Main Authors:	Huang, Siyi, Ziegler, Carly G.K., Austin, John, Mannoun, Najat, Vukovic, Marko, Ordovas-Montanes, Jose, Shalek, Alex K., von Andrian, Ulrich H.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 21-01-2021
Subjects:	Action Potentials Animals Immunomodulation Inflammation - pathology lymph node Lymph Nodes - immunology Lymph Nodes - innervation Mice neuro-immunology nociceptor Nociceptors - metabolism Optogenetics Peptides - metabolism sensory neuron Sensory Receptor Cells - immunology single-cell RNA-seq Skin - innervation Sympathetic Nervous System - physiology Toll-Like Receptors - agonists Toll-Like Receptors - metabolism nociceptor single-cell RNA-seq sensory neuron neuro-immunology lymph node optogenetics
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Summary:	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. [Display omitted] •Anatomical and molecular identification of lymph node-innervating nociceptors•Demonstration of inflammation-induced plasticity of sensory innervation of lymph nodes•Transcriptome-based identification of nociceptor target cells in lymph node•Optogenetic validation of lymph node target cell modulation by nociceptor activity Peripheral lymph nodes are monitored by a unique assortment of sensory neurons with strong enrichment for peptidergic nociceptors. By combining whole-mount immunolabeling, retrograde neuronal tracing, single-cell genomics, and optogenetic approaches, Huang et al. uncover a bidirectional neuroimmune communication axis in lymph nodes, where sensory neurons not only sense lymph node immune status but also, when activated, modulate gene expression in immune and stromal cells.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 S.H., C.G.K.Z., A.K.S., and U.v.A. conceived the study. S.H. performed and analyzed in vivo experiments with help from J.A. and N.M. for image analysis. C.G.K.Z., with the help of J. O.-M. and M. V., generated scRNA-seq data. C.G.K.Z. analyzed scRNA-seq data. S.H., C.G.K.Z., A.K.S., and U.V.A. interpreted the results. S.H., C.G.K.Z., A.K.S., and U.v.A. wrote manuscript with input from J. O.-M. AUTHOR CONTRIBUTIONS These authors contributed equally Senior author
ISSN:	0092-8674 1097-4172 1097-4172
DOI:	10.1016/j.cell.2020.11.028