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

Panicker SP, Ganguly T, Consolo M, Price V, Mirmirani P, Honda K, Karnik P - PLoS ONE (2012)

Bottom Line: Primary cicatricial alopecia (PCA) is a group of inflammatory hair disorders that cause scarring and permanent hair loss.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, United States of America.

ABSTRACT
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.

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Increased expression of immune and inflammatory genes in PCA.The principal component analysis results for upregulated genes from lymphocytic (A) LPP, (B) CCCA, (C) FFA and (D) neutrophilic (TF) cicatricial alopecia are shown. The normal and unaffected samples are clustered together in each subtype, which suggests that the expression of immune and inflammatory genes is not significantly different among these samples. Most samples from affected scalp areas in patients with PCA are clustered separately from normal controls and from samples of unaffected scalp skin from PCA patients, which suggest that the expression of these genes differs between affected and unaffected samples. The top canonical pathways from gene expression profiles in patients with (E) LPP, (F) CCCA, (G) FFA and (H) TF are shown. Red represents upregulated and green represents downregulated genes in these pathways. The yellow graph line in E, F, G and H represents –log (p values). (I) Heat map of the most significantly altered immune and inflammatory genes in LPP (6 affected and 5 unaffected samples), CCCA, FFA and TF (3 affected and 3 unaffected samples each) is shown. The color bar below indicates the level of expression.
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pone-0038449-g003: Increased expression of immune and inflammatory genes in PCA.The principal component analysis results for upregulated genes from lymphocytic (A) LPP, (B) CCCA, (C) FFA and (D) neutrophilic (TF) cicatricial alopecia are shown. The normal and unaffected samples are clustered together in each subtype, which suggests that the expression of immune and inflammatory genes is not significantly different among these samples. Most samples from affected scalp areas in patients with PCA are clustered separately from normal controls and from samples of unaffected scalp skin from PCA patients, which suggest that the expression of these genes differs between affected and unaffected samples. The top canonical pathways from gene expression profiles in patients with (E) LPP, (F) CCCA, (G) FFA and (H) TF are shown. Red represents upregulated and green represents downregulated genes in these pathways. The yellow graph line in E, F, G and H represents –log (p values). (I) Heat map of the most significantly altered immune and inflammatory genes in LPP (6 affected and 5 unaffected samples), CCCA, FFA and TF (3 affected and 3 unaffected samples each) is shown. The color bar below indicates the level of expression.

Mentions: The comparison of gene expression profiles of PCA scalp skin with healthy control skin by microarray analysis revealed that the most prominently upregulated genes are those involved in the immune and inflammatory responses (Figure 3). A principal component analysis based on all upregulated genes in all samples revealed a near-complete separation of the affected tissue from the unaffected and normal tissue in all PCA subtypes (Figures 3A–3D). As shown in Figures 3A–3D, the unaffected tissue from PCA patients (green ovoid) lies on the same plane as the pooled normal control tissue (N = 10 pooled, represented by the blue ovoid). These data suggest that the expression of inflammatory genes is altered in the affected tissue of PCA patients, and there is no significant difference in the expression of inflammatory genes between the unaffected tissue of PCA patients and normal controls. The differential expression of immune response gene clusters in the affected, but not unaffected, scalp skin of PCA patients suggests that the inflammatory changes occur in the “active disease” and do not represent the earliest changes in PCA pathogenesis.


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

Panicker SP, Ganguly T, Consolo M, Price V, Mirmirani P, Honda K, Karnik P - PLoS ONE (2012)

Increased expression of immune and inflammatory genes in PCA.The principal component analysis results for upregulated genes from lymphocytic (A) LPP, (B) CCCA, (C) FFA and (D) neutrophilic (TF) cicatricial alopecia are shown. The normal and unaffected samples are clustered together in each subtype, which suggests that the expression of immune and inflammatory genes is not significantly different among these samples. Most samples from affected scalp areas in patients with PCA are clustered separately from normal controls and from samples of unaffected scalp skin from PCA patients, which suggest that the expression of these genes differs between affected and unaffected samples. The top canonical pathways from gene expression profiles in patients with (E) LPP, (F) CCCA, (G) FFA and (H) TF are shown. Red represents upregulated and green represents downregulated genes in these pathways. The yellow graph line in E, F, G and H represents –log (p values). (I) Heat map of the most significantly altered immune and inflammatory genes in LPP (6 affected and 5 unaffected samples), CCCA, FFA and TF (3 affected and 3 unaffected samples each) is shown. The color bar below indicates the level of expression.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369908&req=5

pone-0038449-g003: Increased expression of immune and inflammatory genes in PCA.The principal component analysis results for upregulated genes from lymphocytic (A) LPP, (B) CCCA, (C) FFA and (D) neutrophilic (TF) cicatricial alopecia are shown. The normal and unaffected samples are clustered together in each subtype, which suggests that the expression of immune and inflammatory genes is not significantly different among these samples. Most samples from affected scalp areas in patients with PCA are clustered separately from normal controls and from samples of unaffected scalp skin from PCA patients, which suggest that the expression of these genes differs between affected and unaffected samples. The top canonical pathways from gene expression profiles in patients with (E) LPP, (F) CCCA, (G) FFA and (H) TF are shown. Red represents upregulated and green represents downregulated genes in these pathways. The yellow graph line in E, F, G and H represents –log (p values). (I) Heat map of the most significantly altered immune and inflammatory genes in LPP (6 affected and 5 unaffected samples), CCCA, FFA and TF (3 affected and 3 unaffected samples each) is shown. The color bar below indicates the level of expression.
Mentions: The comparison of gene expression profiles of PCA scalp skin with healthy control skin by microarray analysis revealed that the most prominently upregulated genes are those involved in the immune and inflammatory responses (Figure 3). A principal component analysis based on all upregulated genes in all samples revealed a near-complete separation of the affected tissue from the unaffected and normal tissue in all PCA subtypes (Figures 3A–3D). As shown in Figures 3A–3D, the unaffected tissue from PCA patients (green ovoid) lies on the same plane as the pooled normal control tissue (N = 10 pooled, represented by the blue ovoid). These data suggest that the expression of inflammatory genes is altered in the affected tissue of PCA patients, and there is no significant difference in the expression of inflammatory genes between the unaffected tissue of PCA patients and normal controls. The differential expression of immune response gene clusters in the affected, but not unaffected, scalp skin of PCA patients suggests that the inflammatory changes occur in the “active disease” and do not represent the earliest changes in PCA pathogenesis.

Bottom Line: Primary cicatricial alopecia (PCA) is a group of inflammatory hair disorders that cause scarring and permanent hair loss.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus