Sensory Neuron–Expressed TRPC4 Is a Target for the Relief of Psoriasiform Itch and Skin Inflammation in Mice

Lee, Sang Hoon; Tonello, Raquel; Choi, Young In; Jung, Sung Jun; Berta, Temugin

doi:10.1016/j.jid.2020.03.959

Cited by 22 publications

(34 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We generated psoriasiform skin inflammation and itch in mice by application of imiquimod cream, as previously described 12 , 36 . Briefly, mice received a daily topical application of 62.5 mg 5% IMQ cream on the shaved back skin (nape area of 2 × 2 cm) for 7 consecutive days, whereas control mice were treated similarly but with a control vehicle cream (Vaseline).…”

Section: Methodsmentioning

confidence: 99%

“…The alloknesis score was the total number of positive responses elicited by the five stimuli (0-5). For skin inflammation, we evaluated erythema and scaling based on our and other similar studies 12 , 28 , 37 . Briefly, erythema (red taint) and scaling (white plaques) were scored separately on a scale ranging from 0 to 4 according to the degree of severity: 0, absent; 1, mild; 2, moderate; 3, severe; 4, very severe.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, skin from the nape was fixed in 4% paraformaldehyde, embedded in tissue freezing medium, and cut into 20 µm-thick sections on a microtome. The sections were then stained with H&E, and epidermal thickness and number of immune cells were quantified as previously described 12 , 28 .…”

Section: Methodsmentioning

confidence: 99%

“…This solution was then injected intrathecally on days 0 and 5 after the first application of IMQ to investigate the role of CGRP in DRG tissues. A valid spinal puncture and intrathecal delivery of siRNA was confirmed by a reflexive tail flick after needle entry into the subarachnoid space, as previously described 12 , 15 , 45 .…”

Section: Methodsmentioning

confidence: 99%

“…Of particular interest, transient receptor potential (TRP) channels such as TRPV1, TRPA1 and TRPC4 are selectively expressed in nociceptors and emerge as major drivers of acute itch, with TRPV1 underlying histaminergic itch 14 , TRPC4 contributing to histaminergic and serotonergic itch 12 , 15 , and TRPA1 driving most other non-histaminergic itch sensations 16 , 17 . These channels have also shown different contributions to various psoriatic symptoms, with TRPV1 and TRPC4 being detrimental and TRPA1 being beneficial for psoriasis in preclinical studies 11 , 12 , 18 , 19 . Great pharmaceutical efforts have been devoted to the development of small-molecules targeting TRP channels, with TRPV1 antagonists yielding multiple clinical trials 20 .…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Resolvin D3 controls mouse and human TRPV1-positive neurons and preclinical progression of psoriasis

Lee

Tonello

et al. 2020

Theranostics

Self Cite

View full text Add to dashboard Cite

Rationale: Psoriasis is a chronic inflammatory disease caused by a complex interplay between the immune and nervous systems with recurrent scaly skin plaques, thickened stratum corneum, infiltration and activation of inflammatory cells, and itch. Despite an increasing availability of immune therapies, they often have adverse effects, high costs, and dissociated effects on inflammation and itch. Activation of sensory neurons innervating the skin and TRPV1 (transient receptor potential vanilloid 1) are emerging as critical components in the pathogenesis of psoriasis, but little is known about their endogenous inhibitors. Recent studies have demonstrated that resolvins, endogenous lipid mediators derived from omega-3 fatty acids, are potent inhibitors of TRP channels and may offer new therapies for psoriasis without known adverse effects. Methods: We used behavioral, electrophysiological and biochemical approaches to investigate the therapeutic effects of resolvin D3 (RvD3), a novel family member of resolvins, in a preclinical model of psoriasis consisting of repeated topical applications of imiquimod (IMQ) to murine skin, which provokes inflammatory lesions that resemble human psoriasis. Results: We report that RvD3 specifically reduced TRPV1-dependent acute pain and itch in mice. Mechanistically, RvD3 inhibited capsaicin-induced TRPV1 currents in dissociated dorsal root ganglion (DRG) neurons via the N-formyl peptide receptor 2 (i.e. ALX/FPR2), a G-protein coupled receptor. Single systemic administration of RvD3 (2.8 mg/kg) reversed itch after IMQ, and repeated administration largely prevented the development of both psoriasiform itch and skin inflammation with concomitant decreased in calcitonin gene-related peptide (CGRP) expression in DRG neurons. Accordingly, specific knockdown of CGRP in DRG was sufficient to prevent both psoriasiform itch and skin inflammation similar to the effects following RvD3 administration. Finally, we elevated the translational potential of this study by showing that RvD3 significantly inhibited capsaicin-induced TRPV1 activity and CGRP release in human DRG neurons. Conclusions: Our findings demonstrate a novel role for RvD3 in regulating TRPV1/CGRP in mouse and human DRG neurons and identify RvD3 and its neuronal pathways as novel therapeutic targets to treat psoriasis.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Resolvin D3 controls mouse and human TRPV1-positive neurons and preclinical progression of psoriasis

Lee

Tonello

et al. 2020

Theranostics

Self Cite

View full text Add to dashboard Cite

show abstract

Canonical transient receptor potential channels and their modulators: biology, pharmacology and therapeutic potentials

et al. 2021

View full text Add to dashboard Cite

Canonical transient receptor potential channels (TRPCs) are nonselective, high calcium permeability cationic channels. The TRPCs family includes TRPC1, TRPC2, TRPC3, TRPC4, TRPC5, TRPC6, and TRPC7. These channels are widely expressed in the cardiovascular and nervous systems and exist in many other human tissues and cell types, playing several crucial roles in the human physiological and pathological processes. Hence, the emergence of TRPCs modulators can help investigate these channels’ applications in health and disease. It is worth noting that the TRPCs subfamilies have structural and functional similarities, which presents a significant difficulty in screening and discovering of TRPCs modulators. In the past few years, only a limited number of selective modulators of TRPCs were detected; thus, additional research on more potent and more selective TRPCs modulators is needed. The present review focuses on the striking desired therapeutic effects of TRPCs modulators, which provides intel on the structural modification of TRPCs modulators and further pharmacological research. Importantly, TRPCs modulators can significantly facilitate future studies of TRPCs and TRPCs related diseases.

show abstract

Single-cell analysis of dorsal root ganglia reveals metalloproteinase signaling in satellite glial cells and pain

Tonello

Prudente

Lee

et al. 2023

Brain, Behavior, and Immunity

View full text Add to dashboard Cite

Sensory Neuron–Expressed TRPC4 Is a Target for the Relief of Psoriasiform Itch and Skin Inflammation in Mice

Cited by 22 publications

References 46 publications

Resolvin D3 controls mouse and human TRPV1-positive neurons and preclinical progression of psoriasis

Resolvin D3 controls mouse and human TRPV1-positive neurons and preclinical progression of psoriasis

Canonical transient receptor potential channels and their modulators: biology, pharmacology and therapeutic potentials

Single-cell analysis of dorsal root ganglia reveals metalloproteinase signaling in satellite glial cells and pain

Contact Info

Product

Resources

About