Department of Dermatology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
PLoS One. 2012;7(6):e38449. doi: 10.1371/journal.pone.0038449. Epub 2012 Jun 7.
Primary cicatricial alopecia (PCA) is a group of inflammatory hair disorders that cause scarring and permanent hair loss. Previous studies have implicated PPARγ, a transcription factor that integrates lipogenic and inflammatory signals, in the pathogenesis of PCA. However, it is unknown what triggers the inflammatory response in these disorders, whether the inflammation is a primary or secondary event in disease pathogenesis, and whether the inflammatory reaction reflects an autoimmune process. In this paper, we show that the cholesterol biosynthetic pathway is impaired in the skin and hair follicles of PCA patients. Treatment of hair follicle cells with BM15766, a cholesterol biosynthesis inhibitor, or 7-dehydrocholesterol (7-DHC), a sterol precursor, stimulates the expression of pro-inflammatory chemokine genes. Painting of mouse skin with 7-DHC or BM15766 inhibits hair growth, causes follicular plugging and induces the infiltration of inflammatory cells into the interfollicular dermis. Our results demonstrate that cholesterologenic changes within hair follicle cells trigger an innate immune response that is associated with the induction of toll-like receptor (TLR) and interferon (IFN) gene expression, and the recruitment of macrophages that surround the hair follicles and initiate their destruction. These findings reveal a previously unsuspected role for cholesterol precursors in PCA pathogenesis and identify a novel link between sterols and inflammation that may prove transformative in the diagnosis and treatment of these disorders.
原发性瘢痕性脱发（PCA）是一组炎症性毛发疾病，可导致瘢痕和永久性脱发。先前的研究表明，过氧化物酶体增殖物激活受体γ（PPARγ）是一种整合脂生成和炎症信号的转录因子，与 PCA 的发病机制有关。然而，目前尚不清楚这些疾病中是什么引发了炎症反应，炎症是疾病发病机制中的主要事件还是次要事件，以及炎症反应是否反映了自身免疫过程。在本文中，我们表明 PCA 患者的皮肤和毛囊中的胆固醇生物合成途径受损。用胆固醇生物合成抑制剂 BM15766 或固醇前体 7-脱氢胆固醇（7-DHC）处理毛囊细胞会刺激促炎趋化因子基因的表达。用 7-DHC 或 BM15766 涂敷小鼠皮肤会抑制毛发生长，导致毛囊堵塞，并诱导炎症细胞浸润到毛囊间真皮。我们的研究结果表明，毛囊细胞内的胆固醇生成变化会引发先天免疫反应，与 Toll 样受体（TLR）和干扰素（IFN）基因表达的诱导以及包围毛囊并启动其破坏的巨噬细胞的募集有关。这些发现揭示了胆固醇前体在 PCA 发病机制中以前未被怀疑的作用，并确定了固醇和炎症之间的新联系，这可能在这些疾病的诊断和治疗中具有变革性。
