Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio, USA.
J Invest Dermatol. 2011 Jul;131(7):1530-8. doi: 10.1038/jid.2011.60. Epub 2011 Apr 7.
Nervous system involvement in psoriasis pathogenesis is supported by increases in nerve fiber numbers and neuropeptides in psoriatic skin and by reports detailing spontaneous plaque remission following nerve injury. Using the KC-Tie2 psoriasiform mouse model, we investigated the mechanisms by which nerve injury leads to inflammatory skin disease remission. Cutaneous nerves innervating dorsal skin of KC-Tie2 animals were surgically axotomized and beginning 1 day after denervation, CD11c(+) cell numbers decreased by 40% followed by a 30% improvement in acanthosis at 7 days and a 30% decrease in CD4(+) T-cell numbers by 10 days. Restoration of substance P (SP) signaling in denervated KC-Tie2 skin prevented decreases in CD11c(+) and CD4(+) cells, but had no effect on acanthosis; restoration of calcitonin gene-related peptide (CGRP) signaling reversed the improvement in acanthosis and prevented denervated-mediated decreases in CD4(+) cells. Under innervated conditions, small-molecule inhibition of SP in KC-Tie2 animals resulted in similar decreases to those observed following surgical denervation for cutaneous CD11c(+) and CD4(+) cell numbers; whereas small-molecule inhibition of CGRP resulted in significant reductions in CD4(+) cell numbers and acanthosis. These data demonstrate that sensory nerve-derived peptides mediate psoriasiform dendritic cell and T-cell infiltration and acanthosis and introduce targeting nerve-immunocyte/KC interactions as potential psoriasis therapeutic treatment strategies.
神经系统参与银屑病发病机制，这一观点得到了银屑病皮肤中神经纤维数量和神经肽增加的支持，并且有报道详细描述了神经损伤后自发斑块消退的情况。使用 KC-Tie2 银屑病样小鼠模型，我们研究了神经损伤导致炎症性皮肤病缓解的机制。KC-Tie2 动物背部皮肤的感觉神经纤维被手术切断，在去神经支配后 1 天，CD11c(+)细胞数量减少了 40%，随后在第 7 天棘层肥厚改善了 30%，第 10 天 CD4(+)T 细胞数量减少了 30%。在去神经支配的 KC-Tie2 皮肤中恢复 P 物质（SP）信号可防止 CD11c(+)和 CD4(+)细胞减少，但对棘层肥厚没有影响；恢复降钙素基因相关肽（CGRP）信号可逆转棘层肥厚的改善，并防止去神经支配引起的 CD4(+)细胞减少。在有神经支配的情况下，KC-Tie2 动物中 SP 的小分子抑制作用导致皮肤 CD11c(+)和 CD4(+)细胞数量与手术去神经支配后观察到的减少相似；而 CGRP 的小分子抑制作用导致 CD4(+)细胞数量和棘层肥厚显著减少。这些数据表明，感觉神经衍生的肽介导了银屑病样树突状细胞和 T 细胞浸润和棘层肥厚，并提出了靶向神经免疫细胞/KC 相互作用作为潜在的银屑病治疗策略。
