Limits...
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.

Show MeSH

Related in: MedlinePlus

Sterol intermediates of cholesterol biosynthesis trigger an inflammatory response in hair follicle cells.Inflammatory and immune responses were the top biological functions affected by treatment of HHFORS cells with (A) 7-DHC or (B) BM15766. The most significant biological functions affected, their p values and the number of differentially expressed genes (molecules) after each treatment were identified using IPA. The difference between vehicle and 7-DHC or BM15766 treatments was defined as significant if a 1.5-fold or greater difference in the average hybridization signal intensity with a p<0.05 using a two-tailed unpaired t-test was observed. Predicted interaction networks in hair follicle cells after treatment with (C) 7-DHC and (D) BM15766 are shown. The TLR4 gene network was activated after 7-DHC treatment, and the TLR6 network was activated after BM15766 treatment. Solid lines denote a direct relationship, and dotted lines denote an indirect relationship between two genes in the network. A red node denotes an upregulated gene, and a green node denotes a downregulated gene, with the difference in intensity reflecting the degree of change in the expression of differentially expressed genes in our dataset. The inflammatory functions and disease (fx) associated with each TLR network were determined using IPA. See also Table S3. The real-time PCR validation of (E) TLR4, (F) TLR6, (G) IFNα, (H) IFNα7 and (I) NFkB gene expression in 7DHC- and BM15766-treated hair follicle cells (*p<0.05, **p<0.01) is shown. The unpaired t-test was used for statistical analysis.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3369908&req=5

pone-0038449-g005: Sterol intermediates of cholesterol biosynthesis trigger an inflammatory response in hair follicle cells.Inflammatory and immune responses were the top biological functions affected by treatment of HHFORS cells with (A) 7-DHC or (B) BM15766. The most significant biological functions affected, their p values and the number of differentially expressed genes (molecules) after each treatment were identified using IPA. The difference between vehicle and 7-DHC or BM15766 treatments was defined as significant if a 1.5-fold or greater difference in the average hybridization signal intensity with a p<0.05 using a two-tailed unpaired t-test was observed. Predicted interaction networks in hair follicle cells after treatment with (C) 7-DHC and (D) BM15766 are shown. The TLR4 gene network was activated after 7-DHC treatment, and the TLR6 network was activated after BM15766 treatment. Solid lines denote a direct relationship, and dotted lines denote an indirect relationship between two genes in the network. A red node denotes an upregulated gene, and a green node denotes a downregulated gene, with the difference in intensity reflecting the degree of change in the expression of differentially expressed genes in our dataset. The inflammatory functions and disease (fx) associated with each TLR network were determined using IPA. See also Table S3. The real-time PCR validation of (E) TLR4, (F) TLR6, (G) IFNα, (H) IFNα7 and (I) NFkB gene expression in 7DHC- and BM15766-treated hair follicle cells (*p<0.05, **p<0.01) is shown. The unpaired t-test was used for statistical analysis.

Mentions: Treatment of HHFORS cells with 7-DHC or BM15766 induced a pro-inflammatory response, as determined by global gene expression profiling and real-time PCR (Figure 5). An IPA analysis of the microarray data for 7-DHC- or BM15766-treated HHFORS cells revealed a significant increase in the expression of inflammatory genes (Figures 5A & 5B). We found that the most significant pathways affected in 7-DHC-treated cells were the cell mediated-immune response, immune cell trafficking, inflammatory disease, the inflammatory response and the humoral immune response (Figure 5A). The most significant pathways affected in BM15766-treated cells were immune cell trafficking, the inflammatory response, immune cell disease, immunological disease and the hematological response (Figure 5B). Intriguingly, the most significant predicted networks identified by IPA analysis included the TLR4 network in 7-DHC-treated cells (Figure 5C, Table S3) and the TLR6 network (Figure 5D, Table S3) in BM15766-treated cells.


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)

Sterol intermediates of cholesterol biosynthesis trigger an inflammatory response in hair follicle cells.Inflammatory and immune responses were the top biological functions affected by treatment of HHFORS cells with (A) 7-DHC or (B) BM15766. The most significant biological functions affected, their p values and the number of differentially expressed genes (molecules) after each treatment were identified using IPA. The difference between vehicle and 7-DHC or BM15766 treatments was defined as significant if a 1.5-fold or greater difference in the average hybridization signal intensity with a p<0.05 using a two-tailed unpaired t-test was observed. Predicted interaction networks in hair follicle cells after treatment with (C) 7-DHC and (D) BM15766 are shown. The TLR4 gene network was activated after 7-DHC treatment, and the TLR6 network was activated after BM15766 treatment. Solid lines denote a direct relationship, and dotted lines denote an indirect relationship between two genes in the network. A red node denotes an upregulated gene, and a green node denotes a downregulated gene, with the difference in intensity reflecting the degree of change in the expression of differentially expressed genes in our dataset. The inflammatory functions and disease (fx) associated with each TLR network were determined using IPA. See also Table S3. The real-time PCR validation of (E) TLR4, (F) TLR6, (G) IFNα, (H) IFNα7 and (I) NFkB gene expression in 7DHC- and BM15766-treated hair follicle cells (*p<0.05, **p<0.01) is shown. The unpaired t-test was used for statistical analysis.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038449-g005: Sterol intermediates of cholesterol biosynthesis trigger an inflammatory response in hair follicle cells.Inflammatory and immune responses were the top biological functions affected by treatment of HHFORS cells with (A) 7-DHC or (B) BM15766. The most significant biological functions affected, their p values and the number of differentially expressed genes (molecules) after each treatment were identified using IPA. The difference between vehicle and 7-DHC or BM15766 treatments was defined as significant if a 1.5-fold or greater difference in the average hybridization signal intensity with a p<0.05 using a two-tailed unpaired t-test was observed. Predicted interaction networks in hair follicle cells after treatment with (C) 7-DHC and (D) BM15766 are shown. The TLR4 gene network was activated after 7-DHC treatment, and the TLR6 network was activated after BM15766 treatment. Solid lines denote a direct relationship, and dotted lines denote an indirect relationship between two genes in the network. A red node denotes an upregulated gene, and a green node denotes a downregulated gene, with the difference in intensity reflecting the degree of change in the expression of differentially expressed genes in our dataset. The inflammatory functions and disease (fx) associated with each TLR network were determined using IPA. See also Table S3. The real-time PCR validation of (E) TLR4, (F) TLR6, (G) IFNα, (H) IFNα7 and (I) NFkB gene expression in 7DHC- and BM15766-treated hair follicle cells (*p<0.05, **p<0.01) is shown. The unpaired t-test was used for statistical analysis.
Mentions: Treatment of HHFORS cells with 7-DHC or BM15766 induced a pro-inflammatory response, as determined by global gene expression profiling and real-time PCR (Figure 5). An IPA analysis of the microarray data for 7-DHC- or BM15766-treated HHFORS cells revealed a significant increase in the expression of inflammatory genes (Figures 5A & 5B). We found that the most significant pathways affected in 7-DHC-treated cells were the cell mediated-immune response, immune cell trafficking, inflammatory disease, the inflammatory response and the humoral immune response (Figure 5A). The most significant pathways affected in BM15766-treated cells were immune cell trafficking, the inflammatory response, immune cell disease, immunological disease and the hematological response (Figure 5B). Intriguingly, the most significant predicted networks identified by IPA analysis included the TLR4 network in 7-DHC-treated cells (Figure 5C, Table S3) and the TLR6 network (Figure 5D, Table S3) in BM15766-treated cells.

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