Department of Dermatology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Institute of Dermatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Immunol. 2022 May 10;13:865704. doi: 10.3389/fimmu.2022.865704. eCollection 2022.
Xanthoma pathogenesis is speculated to be associated with oxidized low-density lipoprotein (ox-LDL) deposition, although this remains unclear. Most patients with diffuse plane xanthomas present elevated blood lipid levels, and they benefit from treatment with oral lipid-lowering agents. However, there is no available treatment for diffuse normolipemic plane xanthoma (DNPX). In this study, for the first time, we used a topical simvastatin ointment to treat DNPX in three pediatric patients and observed favorable results. Immunofluorescence staining showed that the pyroptotic pathway was significantly attenuated after topical simvastatin application on the skin lesions of the patients. As ox-LDL deposition was observed in the lesions, we used ox-LDL to build a foam cell model . In the ox-LDL-induced foam cell formation, simvastatin consistently inhibited pyroptotic activation and inflammation in the macrophages. Additionally, the overexpression of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) or 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase (HMGCR), the known target of statins, reversed the effects of simvastatin. Moreover, gasdermin D (GSDMD) or HMGCR knockdown inhibited ox-LDL-induced pyroptosis. Furthermore, the immunoprecipitation results confirmed the interaction between NLRP3 and HMGCR, and this interaction was inhibited by simvastatin. In conclusion, we demonstrated that topical application of simvastatin ointment might be a promising treatment for DNPX skin lesions and that this therapeutic effect may be related to pyroptosis inhibition HMGCR inhibition in foam cells. Moreover, xanthoma pathogenesis might be associated with ox-LDL deposition and inflammation.
黄瘤病的发病机制推测与氧化型低密度脂蛋白（ox-LDL）沉积有关，但目前仍不清楚。大多数弥漫性平面黄瘤患者存在血脂升高，口服降脂药物治疗有效。然而，弥漫性正常脂平面黄瘤（DNPX）尚无有效治疗方法。本研究首次使用局部辛伐他汀软膏治疗 3 例儿科 DNPX 患者，观察到良好的疗效。免疫荧光染色显示，局部应用辛伐他汀后，患者皮肤病变中的细胞焦亡途径明显减弱。由于在病变中观察到 ox-LDL 沉积，我们使用 ox-LDL 构建泡沫细胞模型。在 ox-LDL 诱导的泡沫细胞形成中，辛伐他汀始终抑制巨噬细胞中的细胞焦亡激活和炎症。此外，核苷酸结合寡聚结构域样受体蛋白 3（NLRP3）或 3-羟基-3-甲基戊二酰基辅酶 A（HMG-CoA）还原酶（HMGCR）的过表达（他汀类药物的已知靶点）逆转了辛伐他汀的作用。此外，gasdermin D（GSDMD）或 HMGCR 敲低抑制 ox-LDL 诱导的细胞焦亡。此外，免疫沉淀结果证实了 NLRP3 和 HMGCR 之间的相互作用，这种相互作用被辛伐他汀抑制。总之，我们表明局部应用辛伐他汀软膏可能是治疗 DNPX 皮肤病变的一种有前途的方法，这种治疗效果可能与泡沫细胞中的细胞焦亡抑制和 HMGCR 抑制有关。此外，黄瘤病的发病机制可能与 ox-LDL 沉积和炎症有关。
