Interleukin-31-mediated photoablation of pruritogenic epidermal neurons reduces itch-associated behaviours in mice

Nocchi, Linda; Roy, Nainika; D'Attilia, Mariangela; Dhandapani, Rahul; Maffei, Mariano; Traista, Andrei; Castaldi, Laura; Perlas, Emerald; Chadick, Cora H.; Heppenstall, Paul A.

doi:10.1038/s41551-018-0328-5

Cited by 18 publications

(16 citation statements)

References 71 publications

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“…Finally, poison ivy‐mediated skin inflammation promotes IL‐33 release which, by binding to neuron‐expressing ST2, triggers scratching reflex . Both found in DRGs, IL‐4R and IL‐13R activation also mediate itch .…”

Section: Endogenous Triggersmentioning

confidence: 99%

Profiling of how nociceptor neurons detect danger – new and old foes

et al. 2019

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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.

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Section: Endogenous Triggersmentioning

confidence: 99%

Profiling of how nociceptor neurons detect danger – new and old foes

et al. 2019

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“…[7; 36; 55] This is in agreement with our previous study using interleukin-31 (IL-31) as a ligand to target pruriceptors in the skin. Like NGF receptors, IL-31 receptors are highly expressed in keratinocytes, however we found that IL-31-guided photoablation induced keratinocyte cell death only at very high concentrations, and at much higher light intensities than those used here [44]. This would suggest that neurons are more sensitive to IR700 induced photoablation than other cells in the skin.…”

Section: Discussionmentioning

confidence: 52%

“…The hindpaw, the knee or the tail of the mice were treated for 3 consecutive days with NGF R121W -SNAP (5 µM) coupled to BG-IR700 (15 µM) (20 μl and 10 μl for paw and knee injections, respectively, and 20 μl for microemulsion application). Depending on the experiment, the coupling reaction was delivered by injection, or topically using a microemulsion, as described previously [44]. Twenty minutes after delivery, near infrared light at 690nm was applied to the treated skin for 1 minute, at 120-150 J/cm 2 (PSU-III-FDA diode laser, CNI Laser, China).…”

Section: In-vivo Photoablationmentioning

confidence: 99%

NGF-mediated photoablation of nociceptors reduces pain behavior in mice

Nocchi¹,

Portulano²,

Franciosa³

et al. 2019

Preprint

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Nerve growth factor (NGF) and its receptors TrkA and p75 play a key role in the development and function of peripheral nociceptive neurons. Here we describe novel technology to selectively photoablate TrkA positive nociceptors through delivery of a phototoxic agent coupled to an engineered NGF ligand and subsequent near infrared (NIR) illumination. We demonstrate that this approach allows for on demand and localized reversal of pain behaviors in mouse models of acute, inflammatory, neuropathic and joint pain. To target peripheral nociceptors we generated a SNAP-tagged NGF derivative, NGF R121W that binds to TrkA/p75 receptors but does not provoke signaling in TrkA positive cells or elicit pain behaviors in mice. NGF R121W-SNAP was coupled to the photosensitizer IRDye®700DX phthalocyanine (IR700) and injected subcutaneously. Following NIR illumination of the injected area, behavioral responses to nociceptive mechanical and sustained thermal stimuli, but not innocuous stimuli, were substantially reduced. Similarly, in models of inflammatory, osteoarthritic and neuropathic pain, mechanical hypersensitivity was abolished for three weeks following a single treatment regime. We demonstrate that this loss of pain behavior coincides with the retraction of neurons from the skin which then re-innervate the epidermis after 3 weeks corresponding with the return of mechanical hypersensitivity. Thus NGF R121W-SNAP -mediated photoablation is a minimally invasive approach to reversibly silence nociceptor input from the periphery, and control pain and hypersensitivity to mechanical stimuli.

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“…Depending on the experiment, the coupling reaction was delivered by injection, or topically using a microemulsion, as described previously. 44 Twenty minutes after delivery, NIR light at 690 nm was applied to the treated skin for 1 minute, at 120 to 150 J/cm 2 (PSU-III-FDA diode laser, CNI Laser, China). Behavioral tests were performed starting from 1 day after the last photoablation.…”

Section: Methodsmentioning

confidence: 99%