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.
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.
Cell. 2021 Jan 21;184(2):441-459.e25. doi: 10.1016/j.cell.2020.11.028. Epub 2020 Dec 16.
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.
屏障组织的免疫反应部分受到伤害感受器的调节。伤害感受器的消融会改变外周部位和引流淋巴结（LN）中的局部免疫反应。伤害感受器依赖性调节 LN 功能的机制和意义尚不清楚。我们使用高分辨率成像、病毒追踪、单细胞转录组学和光遗传学，鉴定并功能测试了一个对淋巴源性炎症信号有反应的感觉神经免疫回路。转录组学分析显示，多个感觉神经元亚群，主要是肽能伤害感受器，支配 LN，与支配周围皮肤的神经元不同。为了揭示可能与支配 LN 的感觉神经元相互作用的 LN 驻留细胞，我们生成了一个 LN 单细胞转录组学图谱，并提名了伤害感受器的靶细胞群和相互作用模式。对支配 LN 的感觉纤维进行光遗传学刺激，会迅速触发预测的相互作用细胞类型（特别是内皮细胞、基质细胞和固有白细胞）的转录变化。因此，独特的感觉神经元群体监测外周 LN，并可能局部调节基因表达。
