SLURP1 and SLURP2 are both small secreted members of the Ly6/u-PAR family of proteins and are highly expressed in keratinocytes. Loss-of-function mutations in SLURP1 lead to a rare autosomal recessive palmoplantar keratoderma (PPK), Mal de Meleda (MdM), which is characterized by diffuse, yellowish palmoplantar hyperkeratosis. Some individuals with MdM experience pain in conjunction with the hyperkeratosis that has been attributed to fissures or microbial superinfection within the affected skin. By comparison, other hereditary PPKs such as pachyonychia congenita and Olmsted syndrome show prevalent pain in PPK lesions. Two mouse models of MdM, Slurp1 knock-out and Slurp2X knock-out, exhibit robust PPK in all four paws. However, whether the sensory experience of these animals includes augmented pain sensitivity remains unexplored. In this study, we demonstrate that both models exhibit hypersensitivity to mechanical and thermal stimuli as well as spontaneous pain behaviors in males and females. Anatomical analysis revealed slightly reduced glabrous skin epidermal innervation and substantial alterations in palmoplantar skin immune composition in Slurp2X knock-out mice. Primary sensory neurons innervating hindpaw glabrous skin from Slurp2X knock-out mice exhibit increased incidence of spontaneous activity and mechanical hypersensitivity both in vitro and in vivo. Thus, Slurp knock-out mice exhibit polymodal PPK-associated pain that is associated with both immune alterations and neuronal hyperexcitability and might therefore be useful for the identification of therapeutic targets to treat PPK-associated pain.

SLURP1 和 SLURP2 都是 Ly6/u-PAR 蛋白家族的小型分泌成员，在角质形成细胞中高度表达。 SLURP1 的功能缺失突变会导致一种罕见的常染色体隐性遗传性掌跖角化症 (PPK)、Mal de Meleda (MdM)，其特征是弥漫性淡黄色掌跖角化过度。一些患有 MdM 的人会经历与角化过度相关的疼痛，角化过度是由于受影响皮肤内的裂痕或微生物重复感染引起的。相比之下，其他遗传性 PPK，如先天性厚甲症和奥姆斯特德综合征，在 PPK 病变中表现出普遍的疼痛。两种 MdM 小鼠模型（Slurp1 敲除和 Slurp2X 敲除）在所有四个爪子中都表现出强大的 PPK。然而，这些动物的感官体验是否包括增强的疼痛敏感性仍有待探索。在这项研究中，我们证明这两种模型都表现出对机械和热刺激的超敏反应以及男性和女性的自发疼痛行为。解剖学分析显示，Slurp2X 敲除小鼠的无毛皮肤表皮神经支配略有减少，掌跖皮肤免疫成分发生显着改变。 Slurp2X 敲除小鼠后爪无毛皮肤的初级感觉神经元在体外和体内表现出自发活动和机械超敏反应发生率增加。因此，Slurp 敲除小鼠表现出与免疫改变和神经元过度兴奋相关的多模式 PPK 相关疼痛，因此可能有助于识别治疗 PPK 相关疼痛的治疗靶点。