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

Abstract

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.

Characteristics of Pruritus in Various Clinical Variants of Psoriasis: Results of the Multinational, Multicenter, Cross-Sectional Study

“…Other authors suggested disturbances in the endogenous opioid system homeostasis, but there is still no final proof that indeed the observed abnormalities are a primary phenomenon in psoriasis leading to pruritus [ 41 , 42 ]. Recent data also indicated the role of transient receptor potential (TRP) channels, such as TRPV1, TRPV4, or TRPM8, but further studies are needed to confirm their relevance [ 43 , 44 , 45 ].…”

The Role of TRPA1 in Skin Physiology and Pathology

“…Growing evidence has revealed that TRPs are actively involved in the regulation of skin physiology [ 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 ]. TRPV1 expression has been identified in epidermal and hair follicle keratinocytes, dermal mast cells, sebaceous gland-derived sebocytes, and dendritic cells [ 78 , 79 ], which suggest functional roles in homeostatic and ‘sensory’ functions not limited to cutaneous nerve fibers.…”

Activation of GPR18 by Resolvin D2 Relieves Pain and Improves Bladder Function in Cyclophosphamide-Induced Cystitis Through Inhibiting TRPV1

“…RvD2 (10 ng, 100 ng) or vehicle (2% ethanol in PBS) was injected intrathecally as described in previous studies. 18,19 Before using O-1918, the methyl acetate was evaporated under a gentle stream of nitrogen, and vehicle was immediately added. The final concentration of O-1918 was 25 mM.…”