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The host evolves redundant mechanisms to preserve physiological processing and homeostasis. These functions range from sensing internal and external threats, creating a memory of the insult and generating reflexes, which aim to resolve inflammation. Impairment in such functioning leads to chronic inflammatory diseases. By interacting through a common language of ligands and receptors, the immune and sensory nervous systems work in concert to accomplish such protective functions. Whilst this bidirectional communication helps to protect from danger, it can contribute to disease pathophysiology. Thus, the somatosensory nervous system is anatomically positioned within primary and secondary lymphoid tissues and mucosa to modulate immunity directly. Upstream of this interplay, neurons detect danger, which prompts the release of neuropeptides initiating (i) defensive reflexes (ranging from withdrawal response to coughing) and (ii) chemotaxis, adhesion and local infiltration of immune cells. The resulting outcome of such neuro‐immune interplay is still ill‐defined, but consensual findings start to emerge and support neuropeptides not only as blockers of TH1‐mediated immunity but also as drivers of TH2 immune responses. However, the modalities detected by nociceptors revealed broader than mechanical pressure and temperature sensing and include signals as various as cytokines and pathogens to immunoglobulins and even microRNAs. Along these lines, we aggregated various dorsal root ganglion sensory neuron expression profiling datasets supporting such wide‐ranging sensing capabilities to help identifying new danger detection modalities of these cells. Thus, revealing unexpected aspects of nociceptor neuron biology might prompt the identification of novel drivers of immunity, means to resolve inflammation and strategies to safeguard homeostasis.

Diabetes is a common condition characterized by persistent hyperglycemia. High blood sugar primarily affects cells that have a limited capacity to regulate their glucose intake. These cells include capillary endothelial cells in the retina, mesangial cells in the renal glomerulus, Schwann cells, and neurons of the peripheral and central nervous systems. As a result, hyperglycemia leads to largely intractable complications such as retinopathy, nephropathy, hypertension, and neuropathy. Diabetic pain neuropathy is a complex and multifactorial disease that has been associated with poor glycemic control, longer diabetes duration, hypertension, advanced age, smoking status, hypoinsulinemia, and dyslipidemia. While many of the driving factors involved in diabetic pain are still being investigated, they can be broadly classified as either neuron -intrinsic or -extrinsic. In neurons, hyperglycemia impairs the polyol pathway, leading to an overproduction of reactive oxygen species and reactive nitrogen species, an enhanced formation of advanced glycation end products, and a disruption in Na+/K+ ATPase pump function. In terms of the extrinsic pathway, hyperglycemia leads to the generation of both overactive microglia and microangiopathy. The former incites a feed-forward inflammatory loop that hypersensitizes nociceptor neurons, as observed at the onset of diabetic pain neuropathy. The latter reduces neurons' access to oxygen, glucose and nutrients, prompting reductions in nociceptor terminal expression and losses in sensation, as observed in the later stages of diabetic pain neuropathy. Overall, microglia can be seen as potent and long-lasting amplifiers of nociceptor neuron activity, and may therefore constitute a potential therapeutic target in the treatment of diabetic pain neuropathy.

Background Dorsal Root Ganglia (DRG) neurons are derived from the neural crest and mainly innervate the skin, while Jugular Nodose Complex (JNC) neurons originate from the placode and innervate internal organs. These ganglia are composed of highly heterogeneous groups of neurons aimed at assessing and preserving homeostasis. Among other subtypes, nociceptor neurons are specialized in sensing and responding to environmental dangers. As form typically follows function, we hypothesized that JNC and DRG neurons would be phenotypically and transcriptomically different. Methods Mouse JNC and DRG neurons were cultured ex vivo. Using calcium imaging, qPCR and neurite outgrowth assay, we compared the sensitivity of JNC and DRG neurons. Using in-silico analysis of existing RNA sequencing datasets, we confronted our results to transcriptomic differences found between both ganglia. Results We found drastically different expression levels of Transient Receptor Potential (TRP) channels, growth factor receptors and neuropeptides in JNC and DRG neurons. Functionally, naïve JNC neurons’ TRP channels are more sensitive to thermal cues than the ones from DRG neurons. However, DRG neurons showed increased TRP channel responsiveness, neuropeptide release and neurite outgrowth when exposed to Nerve Growth Factor (NGF). In contrast, JNC neurons preferentially responded to Brain-derived neurotrophic factor (BDNF). Conclusion Our data show that JNC and DRG neurons are transcriptomically and functionally unique and that pain sensitivity is different across anatomical sites. Drugs targeting NGF signaling may have limited efficacy to treat visceral pain. Bioelectronics nerve stimulation should also be adjusted to the ganglia being targeted and their different expression profile.

Nociceptors, the high-threshold primary sensory neurons that trigger pain, interact with immune cells in the periphery to modulate innate immune responses. Whether they also participate in adaptive and humoral immunity is, however, not known. In this study, we probed if nociceptors have a role in distinct airway and skin models of allergic inflammation. In both models, the genetic ablation and pharmacological silencing of nociceptors substantially reduced inflammatory cell infiltration to the affected tissue. Moreover, we also found a profound and specific deficit in IgE production in these models of allergic inflammation. Mechanistically, we discovered that the nociceptor-released neuropeptide substance P helped trigger the formation of antibody-secreting cells and their release of IgE. Our findings suggest that nociceptors, in addition to their contributions to innate immunity, play a key role in modulating the adaptive immune response, particularly B cell antibody class switching to IgE.

transducers. For example, transient receptor potential vanilloid type 1 (TRPV1) is an ion channel receptor specialized in noxious heat sensing (≈42-45 °C) and expressed by ≈40% of nociceptors. Once activated, it triggers the uptake of sodium and calcium through its ionic pore, leading to neuron depolarization and to neuropeptides release. [3] The immune and sensory nervous systems work in concert to promote host defense and homeostasis. [4] They share metabolic pathways [5] and interact through a common language of receptors, cytokines, and neuropeptides. While this bidirectional communication is often adaptive, helping to protect from danger, in other settings, it drives chronic inflammatory pathologies. [2] Thus, the somatosensory nervous system is anatomically positioned in primary and secondary lymphoid tissues, and mucosa to modulate immunity. As such, nociceptors were found to detect immunocytesreleased interleukin (IL), such as IL-23 produced during psoriasis, IL-4 released in the context of atopic dermatitis as well as IL-5 and immunoglobulin E (IgE) released during allergic asthma. [1] Such interaction results in pain hypersensitivity, but also lowers the nociceptor firing threshold and leads to neuropeptide release. [4] These findings strongly suggest that nociceptor neurons are critical drivers of allergy and inflammation in a variety of diseases by responding to immunocytes produced cues. Theselective silencing of nociceptors' response to such cytokines can transform established therapeutic approaches.The sensory nervous and immune systems work in concert to preserve homeostasis. While this endogenous interplay protects from danger, it may drive chronic pathologies. Currently, genetic engineering of neurons remains the primary approach to interfere selectively with this potentially deleterious interplay. However, such manipulations are not feasible in a clinical setting. Here, this work reports a nanotechnology-enabled concept to silence subsets of unmodified nociceptor neurons that exploits their ability to respond to heat via the transient receptor potential vanilloid type 1 (TRPV1) channel. This strategy uses laser stimulation of antibody-coated gold nanoparticles to heat-activate TRPV1, turning this channel into a cell-specific drug-entry port. This delivery method allows transport of a charged cationic derivative of an N-type calcium channel blocker (CNCB-2) into targeted sensory fibers. CNCB-2 delivery blocks neuronal calcium currents and neuropeptides release, resulting in targeted silencing of nociceptors. Finally, this work demonstrates the ability of the approach to probe neuro-immune crosstalk by targeting cytokine-responsive nociceptors and by successfully preventing nociceptorinduced CD8 + T-cells polarization. Overall, this work constitutes the first demonstration of targeted silencing of nociceptor neuron subsets without requiring genetic modification, establishing a strategy for interfering with deleterious neuro-immune interplays.

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