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). Nevertheless, 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. Transcriptomic 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 transcriptomic atlas and nominated nociceptor target populations and interaction modalities. Optogenetic stimulation of LN-innervating sensory fibers triggered rapid transcriptional changes within 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.
Dataset:
We generated a single-cell transcriptomic atlas of steady-state murine iLNs using Seq-Well. To increase coverage of rare LN cell types – i.e., the non-T, non-B cells – which populate the preferentially-innervated LN periphery, we profiled paired LN samples from before and after immuno-magnetic depletion of T and B cells. Following quality filtering and preprocessing, we recovered libraries from 9,622 single cells. Using established methods for unbiased cell type identification, we uncovered 24 distinct cell types representing all major known lymphoid, myeloid and stromal LN populations.
Contributors:
Siyi Huang #, Carly G. K. Ziegler #, John Austin, Najat Mannoun, Marko Vukovic, Jose Ordovas-Montanes, Alex K. Shalek*, and Ulrich H. von Andrian*
# These authors contributed equally to this work
* These senior authors contributed equally to this work
BioRxiv: https://www.biorxiv.org/content/10.1101/833509v1
Peer-reviewed updated version: https://www.cell.com/cell/fulltext/S0092-8674(20)31564-6
