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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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Decreased expression of genes related to cholesterol biosynthesis and lipogenesis in PCA.Principal component analysis of microarray data (downregulated genes) from lymphocytic (1A–1C) and neutrophilic (1D) cicatricial alopecia was performed with the Partek Genomics Suite. The results of the analysis for LPP are shown in 1A, for CCCA in 1B, for FFA in 1C and for TF in 1D. The horizontal axis corresponds to principal component 1 (PC1), the vertical axis corresponds to PC2 and the depth axis corresponds to PC3. The points are colored by group status: blue represents normal samples (pooled), green represents unaffected samples and red represents affected cicatricial alopecia samples. The clustering of data by samples suggests similarities in gene expression profiles. Unaffected and affected samples are clustered together in each subtype, which suggests that the expression profiles of genes involved in cholesterol biosynthesis and lipogenesis are not significantly different among these samples. The normal scalp tissue was significantly different from the unaffected and affected scalp samples from patients with LPP, CCCA, FFA and TF. (E) Heat map of the 39 most significantly downregulated genes in patients with LPP (6 affected and 5 unaffected scalp samples) CCCA, FFA and TF (3 affected and 3 unaffected scalp samples each). The majority of the genes participated in cholesterol biosynthesis. The color bar below indicates the level of expression. (F) Real-time PCR validation of DHCR7 gene expression in normal skin and in the PCA subtypes LPP, CCCA, FFA, TF and DF (*p<0.05, **p<0.01). Compared with normal tissue, DHCR7 expression was significantly decreased in all PCA samples. The unpaired t-test was used for statistical analysis. (G) Real-time PCR validation of EBP gene expression in skin from normal controls and patients with the PCA subtypes LPP, CCCA, FFA, TF and DF (*p<0.05, **p<0.01). EBP expression was significantly decreased in the PCA subtypes TF, FFA and CCCA but not in DC, FD or LPP. The unpaired t-test was used for statistical analysis. See also Figure S1 and Table S1.
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pone-0038449-g001: Decreased expression of genes related to cholesterol biosynthesis and lipogenesis in PCA.Principal component analysis of microarray data (downregulated genes) from lymphocytic (1A–1C) and neutrophilic (1D) cicatricial alopecia was performed with the Partek Genomics Suite. The results of the analysis for LPP are shown in 1A, for CCCA in 1B, for FFA in 1C and for TF in 1D. The horizontal axis corresponds to principal component 1 (PC1), the vertical axis corresponds to PC2 and the depth axis corresponds to PC3. The points are colored by group status: blue represents normal samples (pooled), green represents unaffected samples and red represents affected cicatricial alopecia samples. The clustering of data by samples suggests similarities in gene expression profiles. Unaffected and affected samples are clustered together in each subtype, which suggests that the expression profiles of genes involved in cholesterol biosynthesis and lipogenesis are not significantly different among these samples. The normal scalp tissue was significantly different from the unaffected and affected scalp samples from patients with LPP, CCCA, FFA and TF. (E) Heat map of the 39 most significantly downregulated genes in patients with LPP (6 affected and 5 unaffected scalp samples) CCCA, FFA and TF (3 affected and 3 unaffected scalp samples each). The majority of the genes participated in cholesterol biosynthesis. The color bar below indicates the level of expression. (F) Real-time PCR validation of DHCR7 gene expression in normal skin and in the PCA subtypes LPP, CCCA, FFA, TF and DF (*p<0.05, **p<0.01). Compared with normal tissue, DHCR7 expression was significantly decreased in all PCA samples. The unpaired t-test was used for statistical analysis. (G) Real-time PCR validation of EBP gene expression in skin from normal controls and patients with the PCA subtypes LPP, CCCA, FFA, TF and DF (*p<0.05, **p<0.01). EBP expression was significantly decreased in the PCA subtypes TF, FFA and CCCA but not in DC, FD or LPP. The unpaired t-test was used for statistical analysis. See also Figure S1 and Table S1.

Mentions: To identify the pathways underlying PCA pathogenesis, we analyzed the gene expression profiles of paired unaffected (non-lesional) and affected (lesional) scalp tissues from 12 lymphocytic (LPP, CCCA, FFA) and 3 neutrophilic (TF) PCA patients. These tissues were compared to normal scalp tissue (N = 10 pooled) from healthy individuals using Affymetrix microarrays. Principal component analysis based on all downregulated genes and all samples revealed a 68.5% variation between diseased and normal samples in the first two principal components (Figure 1A–1D). The unaffected (green ovoid) and affected (red ovoid) samples in each PCA subset, including LPP (Figure 1A), CCCA (Figure 1B), FFA (Figure 1C) and TF (Figure 1D), formed distinct groups and showed a partial overlap. In contrast, the normal controls (N = 10 pooled, blue ovoid) were well separated from both the unaffected and the affected samples from the patients (Figure 1A–1D). In LPP (Figure 1A), the normal controls lie within the plane of unaffected samples. This is due to the smaller number of gene expression changes in unaffected LPP compared to normal samples. These analyses indicate a distinct gene expression profile of unaffected scalp skin in all PCA subtypes. This gene expression profile has some similarities to that of the affected scalp skin from the same patients, but is markedly different from the profile of normal healthy controls.


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)

Decreased expression of genes related to cholesterol biosynthesis and lipogenesis in PCA.Principal component analysis of microarray data (downregulated genes) from lymphocytic (1A–1C) and neutrophilic (1D) cicatricial alopecia was performed with the Partek Genomics Suite. The results of the analysis for LPP are shown in 1A, for CCCA in 1B, for FFA in 1C and for TF in 1D. The horizontal axis corresponds to principal component 1 (PC1), the vertical axis corresponds to PC2 and the depth axis corresponds to PC3. The points are colored by group status: blue represents normal samples (pooled), green represents unaffected samples and red represents affected cicatricial alopecia samples. The clustering of data by samples suggests similarities in gene expression profiles. Unaffected and affected samples are clustered together in each subtype, which suggests that the expression profiles of genes involved in cholesterol biosynthesis and lipogenesis are not significantly different among these samples. The normal scalp tissue was significantly different from the unaffected and affected scalp samples from patients with LPP, CCCA, FFA and TF. (E) Heat map of the 39 most significantly downregulated genes in patients with LPP (6 affected and 5 unaffected scalp samples) CCCA, FFA and TF (3 affected and 3 unaffected scalp samples each). The majority of the genes participated in cholesterol biosynthesis. The color bar below indicates the level of expression. (F) Real-time PCR validation of DHCR7 gene expression in normal skin and in the PCA subtypes LPP, CCCA, FFA, TF and DF (*p<0.05, **p<0.01). Compared with normal tissue, DHCR7 expression was significantly decreased in all PCA samples. The unpaired t-test was used for statistical analysis. (G) Real-time PCR validation of EBP gene expression in skin from normal controls and patients with the PCA subtypes LPP, CCCA, FFA, TF and DF (*p<0.05, **p<0.01). EBP expression was significantly decreased in the PCA subtypes TF, FFA and CCCA but not in DC, FD or LPP. The unpaired t-test was used for statistical analysis. See also Figure S1 and Table S1.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038449-g001: Decreased expression of genes related to cholesterol biosynthesis and lipogenesis in PCA.Principal component analysis of microarray data (downregulated genes) from lymphocytic (1A–1C) and neutrophilic (1D) cicatricial alopecia was performed with the Partek Genomics Suite. The results of the analysis for LPP are shown in 1A, for CCCA in 1B, for FFA in 1C and for TF in 1D. The horizontal axis corresponds to principal component 1 (PC1), the vertical axis corresponds to PC2 and the depth axis corresponds to PC3. The points are colored by group status: blue represents normal samples (pooled), green represents unaffected samples and red represents affected cicatricial alopecia samples. The clustering of data by samples suggests similarities in gene expression profiles. Unaffected and affected samples are clustered together in each subtype, which suggests that the expression profiles of genes involved in cholesterol biosynthesis and lipogenesis are not significantly different among these samples. The normal scalp tissue was significantly different from the unaffected and affected scalp samples from patients with LPP, CCCA, FFA and TF. (E) Heat map of the 39 most significantly downregulated genes in patients with LPP (6 affected and 5 unaffected scalp samples) CCCA, FFA and TF (3 affected and 3 unaffected scalp samples each). The majority of the genes participated in cholesterol biosynthesis. The color bar below indicates the level of expression. (F) Real-time PCR validation of DHCR7 gene expression in normal skin and in the PCA subtypes LPP, CCCA, FFA, TF and DF (*p<0.05, **p<0.01). Compared with normal tissue, DHCR7 expression was significantly decreased in all PCA samples. The unpaired t-test was used for statistical analysis. (G) Real-time PCR validation of EBP gene expression in skin from normal controls and patients with the PCA subtypes LPP, CCCA, FFA, TF and DF (*p<0.05, **p<0.01). EBP expression was significantly decreased in the PCA subtypes TF, FFA and CCCA but not in DC, FD or LPP. The unpaired t-test was used for statistical analysis. See also Figure S1 and Table S1.
Mentions: To identify the pathways underlying PCA pathogenesis, we analyzed the gene expression profiles of paired unaffected (non-lesional) and affected (lesional) scalp tissues from 12 lymphocytic (LPP, CCCA, FFA) and 3 neutrophilic (TF) PCA patients. These tissues were compared to normal scalp tissue (N = 10 pooled) from healthy individuals using Affymetrix microarrays. Principal component analysis based on all downregulated genes and all samples revealed a 68.5% variation between diseased and normal samples in the first two principal components (Figure 1A–1D). The unaffected (green ovoid) and affected (red ovoid) samples in each PCA subset, including LPP (Figure 1A), CCCA (Figure 1B), FFA (Figure 1C) and TF (Figure 1D), formed distinct groups and showed a partial overlap. In contrast, the normal controls (N = 10 pooled, blue ovoid) were well separated from both the unaffected and the affected samples from the patients (Figure 1A–1D). In LPP (Figure 1A), the normal controls lie within the plane of unaffected samples. This is due to the smaller number of gene expression changes in unaffected LPP compared to normal samples. These analyses indicate a distinct gene expression profile of unaffected scalp skin in all PCA subtypes. This gene expression profile has some similarities to that of the affected scalp skin from the same patients, but is markedly different from the profile of normal healthy controls.

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