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./nMethods: 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./nResults: 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./nConclusions: 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.

中文翻译：

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Resolvin D3 控制小鼠和人类 TRPV1 阳性神经元以及银屑病的临床前进展


理由：牛皮癣是一种慢性炎症性疾病，由免疫和神经系统之间复杂的相互作用引起，具有复发性鳞状皮肤斑块、角质层增厚、炎症细胞浸润和激活以及瘙痒。尽管免疫疗法的可用性越来越高，但它们通常具有副作用、成本高以及对炎症和瘙痒的独立影响。支配皮肤的感觉神经元和 TRPV1（瞬时受体电位香草酸 1）的激活正在成为银屑病发病机制的关键组成部分，但人们对其内源性抑制剂知之甚少。最近的研究表明，溶解素（源自 omega-3 脂肪酸的内源性脂质介质）是 TRP 通道的有效抑制剂，可能为银屑病提供新疗法，且没有已知的副作用。/n方法：我们使用行为、电生理学和生化方法来研究Resolvin D3 (RvD3)（一种新的 Resolvins 家族成员）在银屑病临床前模型中的治疗效果，该模型包括在小鼠皮肤上重复局部应用咪喹莫特 (IMQ)，从而引发类似于人类银屑病的炎症病变。/n 结果：我们报告说，RvD3 特异性地减轻了小鼠 TRPV1 依赖性急性疼痛和瘙痒。从机制上讲，RvD3 通过 N-甲酰肽受体 2（即 ALX/FPR2）（一种 G 蛋白偶联受体）抑制解离背根神经节 (DRG) 神经元中辣椒素诱导的 TRPV1 电流。 RvD3 的单次全身给药 (2.8 mg/kg）可逆转IMQ后的瘙痒，重复给药在很大程度上阻止了银屑病瘙痒和皮肤炎症的发展，同时降低了DRG神经元中降钙素基因相关肽（CGRP）的表达。因此，DRG 中 CGRP 的特异性敲低足以预防银屑病瘙痒和皮肤炎症，类似于 RvD3 给药后的效果。最后，我们通过证明 RvD3 显着抑制辣椒素诱导的 TRPV1 活性和人类 DRG 神经元中 CGRP 的释放，提高了本研究的转化潜力。/n 结论：我们的研究结果证明了 RvD3 在调节小鼠和人类 TRPV1/CGRP 方面的新作用DRG 神经元并确定 RvD3 及其神经元通路作为治疗牛皮癣的新治疗靶点。