Cutaneous TRPV1+ Neurons Trigger Protective Innate Type 17 Anticipatory Immunity

Abstract

Highlights d Cutaneous TRPV1 + neuron activation is sufficient to initiate type 17 inflammation d Cutaneous TRPV1 + neuron activation augments local host defense d Type 17 innate immunity via nerve reflex provides regional anticipatory immunity

Cellular and molecular mechanisms of antifungal innate immunity at epithelial barriers: The role of C‐type lectin receptors

“…in the absence of damage‐ or pathogen‐associated molecular patterns) is sufficient to elicit CGRP‐mediated IL‐17 production at the stimulation site as well as adjacent sites through a nerve reflex arc. These events lead to enhanced protection against C. albicans and Staphylococcus aureus skin infections [61]. Heterologous protection against C. albicans can also be promoted by colonization of the skin with other commensals.…”

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

“…The downstream output is typically measured by electrophysiology, calcium imaging and behavioral assays (Kim et al, 2017). Only recently has this approach been applied to interrogate neuronal 730 circuits underlying neuromodulation of peripheral tissues (Chang et al, 2015;Cohen et al, 2019;Mickle et al, 2019;Murray et al, 2019;Rajendran et al, 2019;Williams et al, 2016;Zeng et al, 2015). In those few cases, optogenetics-induced effects were generally assessed based on specific hypotheses, such as select physiological or cellular functions.…”

“…Although sensory neurons by definition relay information from the periphery to the CNS, recent studies have shown that sensory neurons are not exclusively afferent, but also possess the ability to act in a motor neuron-like, or efferent, fashion via a process known as the "axon reflex" (Chiu et al, 2012;Cohen et al, 2019;Richardson and 750 Vasko, 2002). That is, action potentials generated locally at peripheral terminals of sensory neurons can backpropagate to neighboring axonal collaterals once they reach axonal branch points.…”

“…That is, action potentials generated locally at peripheral terminals of sensory neurons can backpropagate to neighboring axonal collaterals once they reach axonal branch points. For example, in a recent study, optogenetic stimulation of cutaneous TRPV1 + sensory neurons was sufficient to stimulate local IL-17 mediated inflammation and enhanced anti-bacterial immune responses, which appeared to depend largely on the efferent function of the sensory neurons (Cohen et al, 2019). It remains to be determined (but seems likely) whether axon reflexes occur also in LN-innervating neurons, but it is conceivable that this mechanism could result in local release of neurotransmitters from peripheral terminals of activated LN-innervating neurons and impact the function of LN resident cells, without engaging the CNS.…”

“…In addition, sensory neurons might also impact LNs through their conventional afferent functions by initiating monosynaptic or polysynaptic reflex-like neural circuits in the CNS, which, in visceral organs, culminates in motor output from the autonomic nervous system mediated by sympathetic 760 and/or parasympathetic neurons. Both efferent and afferent functions of sensory neurons have been implicated in immunomodulation (Baral et al, 2019;Chavan et al, 2017;Cohen et al, 2019), but their relative contributions to any specific immunological process are still poorly understood. Since LNs are dually innervated by sensory and sympathetic neurons, the robust modulatory effects of selective optogenetic stimulation of LN-innervating sensory neurons observed here could in theory result from either their atypical efferent or their more conventional afferent functions, or both.…”