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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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Ingenuity Pathways Analysis of the top toxic pathways in cicatricial alopecia.IPA-Tox®, a data analysis capability tool within the Ingenuity Pathways Analysis, was used to analyze the microarray data and to determine the toxicity associated with the observed gene expression changes in PCA. The figure shows the top toxicity lists (Toxlists) associated with gene expression changes in samples from unaffected and affected scalp areas in patients with LPP, CCCA, FFA and TF. Cholesterol biosynthesis appears to be the most significant toxicity-related pathway associated with the lymphocytic PCA subtypes.
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pone-0038449-g002: Ingenuity Pathways Analysis of the top toxic pathways in cicatricial alopecia.IPA-Tox®, a data analysis capability tool within the Ingenuity Pathways Analysis, was used to analyze the microarray data and to determine the toxicity associated with the observed gene expression changes in PCA. The figure shows the top toxicity lists (Toxlists) associated with gene expression changes in samples from unaffected and affected scalp areas in patients with LPP, CCCA, FFA and TF. Cholesterol biosynthesis appears to be the most significant toxicity-related pathway associated with the lymphocytic PCA subtypes.

Mentions: To determine the biological relevance of the gene expression changes in PCA, we analyzed the microarray data with the Ingenuity Pathway Analysis (IPA) software (www.ingenuity.com, Ingenuity Systems Inc., Redwood City, CA, USA). IPA provides the ability to map differentially expressed genes to fixed canonical pathways and Toxlists. IPA-Tox® is a data analysis capability within IPA that identifies biological mechanisms that are related to toxicity (Toxlists) (on a molecular, cellular, and biochemical level). Figure 2 summarizes the most significant Toxlists associated with the gene expression changes observed in unaffected and affected tissues from patients with LPP, CCCA, FFA and TF. Cholesterol biosynthesis appears at the top of the Toxlist (Figure 2A–2F) suggesting that it is the most significant toxic pathway associated with the lymphocytic PCA subtypes. The other significant pathways in lymphocytic PCA include fatty acid metabolism, oxidative stress response, mitochondrial dysfunction and LXR/RXR activation. In contrast, the oxidative stress response and hypoxia-inducible factor (HIF) signaling are the most significant toxic pathways associated with neutrophilic PCA (Figure 2G–2H). As shown in Figure 2A–2F, although the Toxlists are remarkably similar, there are also distinct differences between the different subtypes of lymphocytic PCA.


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)

Ingenuity Pathways Analysis of the top toxic pathways in cicatricial alopecia.IPA-Tox®, a data analysis capability tool within the Ingenuity Pathways Analysis, was used to analyze the microarray data and to determine the toxicity associated with the observed gene expression changes in PCA. The figure shows the top toxicity lists (Toxlists) associated with gene expression changes in samples from unaffected and affected scalp areas in patients with LPP, CCCA, FFA and TF. Cholesterol biosynthesis appears to be the most significant toxicity-related pathway associated with the lymphocytic PCA subtypes.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038449-g002: Ingenuity Pathways Analysis of the top toxic pathways in cicatricial alopecia.IPA-Tox®, a data analysis capability tool within the Ingenuity Pathways Analysis, was used to analyze the microarray data and to determine the toxicity associated with the observed gene expression changes in PCA. The figure shows the top toxicity lists (Toxlists) associated with gene expression changes in samples from unaffected and affected scalp areas in patients with LPP, CCCA, FFA and TF. Cholesterol biosynthesis appears to be the most significant toxicity-related pathway associated with the lymphocytic PCA subtypes.
Mentions: To determine the biological relevance of the gene expression changes in PCA, we analyzed the microarray data with the Ingenuity Pathway Analysis (IPA) software (www.ingenuity.com, Ingenuity Systems Inc., Redwood City, CA, USA). IPA provides the ability to map differentially expressed genes to fixed canonical pathways and Toxlists. IPA-Tox® is a data analysis capability within IPA that identifies biological mechanisms that are related to toxicity (Toxlists) (on a molecular, cellular, and biochemical level). Figure 2 summarizes the most significant Toxlists associated with the gene expression changes observed in unaffected and affected tissues from patients with LPP, CCCA, FFA and TF. Cholesterol biosynthesis appears at the top of the Toxlist (Figure 2A–2F) suggesting that it is the most significant toxic pathway associated with the lymphocytic PCA subtypes. The other significant pathways in lymphocytic PCA include fatty acid metabolism, oxidative stress response, mitochondrial dysfunction and LXR/RXR activation. In contrast, the oxidative stress response and hypoxia-inducible factor (HIF) signaling are the most significant toxic pathways associated with neutrophilic PCA (Figure 2G–2H). As shown in Figure 2A–2F, although the Toxlists are remarkably similar, there are also distinct differences between the different subtypes of lymphocytic PCA.

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