Epineural optogenetic activation of nociceptors initiates and amplifies inflammation

Michoud, Frédéric; Seehus, Corey R.; Schonle, Philipp; Brun, Noé; Taub, Daniel G.; Zhang, Zihe; Jain, Aakanksha; Furfaro, Ivan; Akouissi, Outman; Moon, Rachel; Meier, Pascale; Galan, Katia; Doyle, Benjamin; Tetreault, Michael; Talbot, Sébastien; Browne, Liam E.; Huang, Qiuting; Woolf, Clifford J.; Lacour, Stéphanie

doi:10.1038/s41587-020-0673-2

Cited by 70 publications

(53 citation statements)

References 42 publications

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“…Similarly, recent evidence points to a role of lung nociceptor neurons in initiating downstream Th2 cell activation and subsequent allergen-induced inflammation (81). Another recent study using optogenetic activation of nociceptors in naïve mice demonstrated that levels of dDCs and gd, ab T cells and DETCs increased in the skin after optogenetic stimulation (82). Further, optogenetic nociceptor stimulation in mice treated with complete Freund's adjuvant induced significant additional increases in the numbers of gd and ab T cells in the inflamed skin indicating that antidromic nociceptor activation alone is sufficient to induce and potentiate inflammation (82).…”

Section: Immune Cell Regulation By Sensory Neurons In the Skinmentioning

confidence: 94%

“…Another recent study using optogenetic activation of nociceptors in naïve mice demonstrated that levels of dDCs and gd, ab T cells and DETCs increased in the skin after optogenetic stimulation (82). Further, optogenetic nociceptor stimulation in mice treated with complete Freund's adjuvant induced significant additional increases in the numbers of gd and ab T cells in the inflamed skin indicating that antidromic nociceptor activation alone is sufficient to induce and potentiate inflammation (82). This study further illustrates the strong links between sensory neurons and immune cells in the skin.…”

Section: Immune Cell Regulation By Sensory Neurons In the Skinmentioning

confidence: 99%

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Cutaneous Neuroimmune Interactions in Peripheral Neuropathic Pain States

2021

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Bidirectional interplay between the peripheral immune and nervous systems plays a crucial role in maintaining homeostasis and responding to noxious stimuli. This crosstalk is facilitated by a variety of cytokines, inflammatory mediators and neuropeptides. Dysregulation of this delicate physiological balance is implicated in the pathological mechanisms of various skin disorders and peripheral neuropathies. The skin is a highly complex biological structure within which peripheral sensory nerve terminals and immune cells colocalise. Herein, we provide an overview of the sensory innervation of the skin and immune cells resident to the skin. We discuss modulation of cutaneous immune response by sensory neurons and their mediators (e.g., nociceptor-derived neuropeptides), and sensory neuron regulation by cutaneous immune cells (e.g., nociceptor sensitization by immune-derived mediators). In particular, we discuss recent findings concerning neuroimmune communication in skin infections, psoriasis, allergic contact dermatitis and atopic dermatitis. We then summarize evidence of neuroimmune mechanisms in the skin in the context of peripheral neuropathic pain states, including chemotherapy-induced peripheral neuropathy, diabetic polyneuropathy, post-herpetic neuralgia, HIV-induced neuropathy, as well as entrapment and traumatic neuropathies. Finally, we highlight the future promise of emerging therapies associated with skin neuroimmune crosstalk in neuropathic pain.

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Section: Immune Cell Regulation By Sensory Neurons In the Skinmentioning

confidence: 94%

Section: Immune Cell Regulation By Sensory Neurons In the Skinmentioning

confidence: 99%

Cutaneous Neuroimmune Interactions in Peripheral Neuropathic Pain States

2021

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“…The targeted mouse genetic (NaV1.8 Cre ::ChR2 fl/wt ; NaV1.8 Cre ::DTA fl/wt ; TRPV1 Cre ::DTA fl/wt ; RAMP1 -/-CD8 T cells) and pharmacological (CGRP, BIBN4096, CGRP8-37, capsaicin, QX-314, BoNT/A) approaches used here are specific for nociceptors 22,29,31,32,[39][40][41][53][54][55][56][57][58][59][60][61] . Thus, BoNT/A, QX-314, and BIBN4096 did not impact either B16F10 survival or CD8 + T-cell function in vitro (Supp.…”

Section: Or Other Ethical Endpoints)mentioning

confidence: 99%

“…Optogenetic activation of skin nociceptor neurons mediate an anticipatory immunity against microbes 39 , and by triggering the antidromic release of peptides, potentiates skin 40 and lung 41 immunity. We used transdermal illumination (3.5 ms, 10Hz, 478nm, 100 mW, delivering ~2-6 mW/mm 2 to a 0.39 NA fiber placed 5-10 mm from the skin, for 20 min) to stimulate tumor-innervating NaV1.8 + neurons optogenetically NaV1.8 Cre ::ChR2 fl/wt mice.…”

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confidence: 99%

Nociceptor neurons impair cancer immunosurveillance

Talbot¹,

Balood²,

Ahmadi³

et al. 2021

Preprint

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Solid tumors are innervated by nerve fibers that arise from the autonomic and sensory peripheral nervous systems. In prostate cancer, doublecortin-expressing neural progenitors initiate autonomic adrenergic neurogenesis1 which facilitates tumor development and dissemination2, via an angiogenic switch that fuels cancer growth3,4. Similarly, a loss of TP53 drives the reprogramming of tumor-innervating sensory nerves into adrenergic neurons in head and neck tumors, which promotes tumor growth5. However, the impact of tumor neo-innervation by pain-initiating sensory neurons remains unclear. We show that melanoma cells interact with nociceptors, increasing neurite outgrowth, responsiveness to noxious ligands, and neuropeptide release. In turn, CGRP, a nociceptor-produced neuropeptide, directly increases exhaustion of cytotoxic CD8+ T-cells (PD1+Lag3+Tim3+IFNγ-), limiting their capacity to eliminate melanoma. Genetic NaV1.8 or TRPV1 lineage ablation, local pharmacological silencing or blockade of neuropeptide release from tumor-innervating nociceptors, and the antagonism of the CGRP receptor RAMP1, all blunt tumor-infiltrating leukocyte exhaustion, and tumor growth, nearly tripling survival of B16F10-inoculated mice. Inversely, CD8+ T-cell exhaustion increased following optogenetic activation of tumor-innervating NaV1.8 neurons+ and was rescued in sensory neuron depleted mice treated with recombinant CGRP. In comparison to wild-type CD8+ T-cells, RAMP1-/- CD8+ T-cells were protected from undergoing exhaustion when co-transplanted into tumor-bearing Rag1 deficient mice. Single-cell RNA sequencing of patient tumors revealed that intratumoral RAMP1-expressing CD8+ T-cells are more exhausted than their RAMP1 negative counterparts. RAMP1 expression in intratumoral CD8+ T-cells was also associated with resistance to immune checkpoint inhibitor treatment, while RAMP1 overexpression within the tumor correlated with a worse clinical prognosis. We conclude that reducing CGRP release from tumor-innervating nociceptors, by eliminating its immunomodulatory action on cytotoxic CD8+ T-cells, constitutes a useful strategy to safeguard anti-tumor immunity.

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“…Possible applications would include bidirectional modulations of neural activities by leveraging electrophysiological or neurotransmitter signals for medications of seizures or Parkinson's disease27,61, 62 . Besides central nervous systems, peripheral neural circuits can also be targeted for medical treatments63,64 . In summary, the results presentedhere provide a viable means for fundamental neuroscience studies and advanced Prigge M, Beyriere F, Tsunoda SP, Mattis J, Yizhar O, et al Red-shifted optogenetic excitation: a tool for fast neural control derived from Volvox carteri.…”

mentioning

confidence: 99%

Colocalized, Bidirectional Optogenetic Modulations in Freely Behaving Mice with a Wireless Dual-Color Optoelectronic Probe

Sheng

2021

Preprint

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The precise control of neural activities at both cellular and circuit levels reveals significant impacts on the fundamental neuroscience explorations and medical applications. Optogenetic methods provide efficient cell-specific modulations, but state-of-the-art technologies lack the ability of simultaneous neural activation and inhibition in a same brain region of freely moving animals. Here we report bidirectional neuronal activity manipulation accomplished by a wireless, dual-color optogenetic probe in synergy with the co-expression of two spectrally distinct opsins (ChrimsonR and stGtACR2) in a rodent model. Based on vertically assembled, thin-film microscale light-emitting diodes (micro-LEDs) on flexible substrates, the dual-color probe shows colocalized red and blue emissions and allows chronic in vivo operations with desirable biocompatibilities. In addition, we discover that neurons co-expressing the two opsins can be deterministically evoked or silenced under red or blue irradiations. Implanted in behaving mice, the wirelessly controlled dual-color probe interferes with dopaminergic neurons in the ventral tegmental area (VTA), increasing or decreasing dopamine levels with colocalized red and blue stimulations. Such bidirectional regulations further generate rewarding and aversive behaviors of freely moving animals in a place preference test. The technologies established here will create numerous opportunities and profound implications for the brain research.

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Epineural optogenetic activation of nociceptors initiates and amplifies inflammation

Cited by 70 publications

References 42 publications

Cutaneous Neuroimmune Interactions in Peripheral Neuropathic Pain States

Cutaneous Neuroimmune Interactions in Peripheral Neuropathic Pain States

Nociceptor neurons impair cancer immunosurveillance

Colocalized, Bidirectional Optogenetic Modulations in Freely Behaving Mice with a Wireless Dual-Color Optoelectronic Probe

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