Sterol intermediates of cholesterol biosynthesis inhibit hair growth and trigger an innate immune response in cicatricial alopecia

• Published in: PloS one 2012-06, Vol.7 (6), p.e38449
• Main Authors: Panicker, Sreejith P, Ganguly, Taneeta, Consolo, Mary, Price, Vera, Mirmirani, Paradi, Honda, Kord, Karnik, Pratima
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Alopecia; Alopecia - genetics; Alopecia - immunology; Alopecia - pathology; Animals; Biological response modifiers; Biology; Biosynthesis; Biosynthetic Pathways - genetics; Cells, Cultured; Chemokines - genetics; Cholesterol; Cholesterol - biosynthesis; Cholesterol - chemistry; Cicatrix - genetics; Cicatrix - immunology; Cicatrix - pathology; Dehydrocholesterols - pharmacology; Dermatology; Dermis; Development and progression; Disorders; Female; Follicles; Gene expression; Gene Expression - drug effects; Gene Expression Profiling; Gene Regulatory Networks; Genes; Growth; Hair; Hair - drug effects; Hair - growth & development; Hair - metabolism; Hair Follicle - drug effects; Hair Follicle - metabolism; Hair Follicle - pathology; Hair loss; Humans; Immune response; Immune system; Immunity, Innate - genetics; Immunity, Innate - immunology; Infiltration; Inflammation; Inflammatory response; Innate immunity; Interferon; Intermediates; Ligands; Lipids; Losses; Macrophages; Male; Medical research; Medicine; Metabolism; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Pathogenesis; Physiological aspects; Piperazines - pharmacology; Principal components analysis; Proteins; Recruitment; Reverse Transcriptase Polymerase Chain Reaction; Scars; Skin; Stem cells; Sterols; Sterols - chemistry; Sterols - metabolism; Toll-like receptors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0038449

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.