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

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 30 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 40 population of sensory neurons that possesses immunomodulatory potential. 840 and Harvard. J.O

Somatotopic Organization and Intensity Dependence in Driving Distinct NPY-Expressing Sympathetic Pathways by Electroacupuncture

“…For example, about 50% nerve fibers within the splanchnic nerve are sensory afferents derived from DRG (Janig and Habler, 2000). With demonstrated sensory innervations in immune organs (Huang et al, 2019), one alternative possibility is that endogenous anti-inflammation roles might operate via sensory axon reflexes, as suggested from inflammation control in other tissues (Fernandes et al, 2012;Pinho-Ribeiro et al, 2018). Here we reported that NPY DBH marks a subset of sympathetic cells, without marking somatosensory or visceral sensory afferents.…”

Fibroblastic reticular cell response to dendritic cells requires coordinated activity of podoplanin, CD44 and CD9

“…We here define TRCs to include all CD31 -PDPN + MAdCAM-1 -FRC subsets (Huang et al, 2019;Rodda et al, 2018;Sitnik et al, 2016). We found that surface expression of podoplanin does not change on LECs (Fig.…”