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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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Sterol intermediates of cholesterol biosynthesis inhibit hair growth and activate the inflammatory response in C57BL/6J mice.(A) Topical 7-DHC and (B) BM15766 treatment inhibited hair growth compared with vehicle treatment (ethanol or DMSO). Hair growth was restored in vehicle-treated but not in 7-DHC and BM15766 treated mice. (C, D) Histology of mouse skin treated with ethanol, DMSO, 7-DHC and BM15766 (20X). H&E staining of vehicle-treated mice showed normal hair follicles and sebaceous glands. In contrast, H&E staining of mice treated with 7-DHC and BM15766 showed hyperkeratosis as well as dystrophic hair follicles and sebaceous glands. Scale bar = 50 µm. (E, F) H&E staining showed peri-follicular and inter-follicular inflammation in mouse skin that had been treated with 7-DHC (40×). At higher magnification (100×), infiltration of tissue histiocytes is observed. (G, F) A higher percentage of F4/80 cells was present in mouse skin treated with 7-DHC (Q5-LR) and BM15766 (Q4-LR) than in the vehicle-treated mouse skin. See also Figures S3 and S4.
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pone-0038449-g006: Sterol intermediates of cholesterol biosynthesis inhibit hair growth and activate the inflammatory response in C57BL/6J mice.(A) Topical 7-DHC and (B) BM15766 treatment inhibited hair growth compared with vehicle treatment (ethanol or DMSO). Hair growth was restored in vehicle-treated but not in 7-DHC and BM15766 treated mice. (C, D) Histology of mouse skin treated with ethanol, DMSO, 7-DHC and BM15766 (20X). H&E staining of vehicle-treated mice showed normal hair follicles and sebaceous glands. In contrast, H&E staining of mice treated with 7-DHC and BM15766 showed hyperkeratosis as well as dystrophic hair follicles and sebaceous glands. Scale bar = 50 µm. (E, F) H&E staining showed peri-follicular and inter-follicular inflammation in mouse skin that had been treated with 7-DHC (40×). At higher magnification (100×), infiltration of tissue histiocytes is observed. (G, F) A higher percentage of F4/80 cells was present in mouse skin treated with 7-DHC (Q5-LR) and BM15766 (Q4-LR) than in the vehicle-treated mouse skin. See also Figures S3 and S4.

Mentions: We next determined whether BM15766 and 7-DHC have the same effects on mouse skin in vivo (Figure 6). Mouse hair cycle stages are naturally synchronized in individual mice. However, animals of the same age and from the same litter can exhibit heterogeneity with respect to hair follicle cycling. Therefore, mice in the telogen phase of hair growth cycle (7 weeks old) were depilated to synchronize their hair cycle stages and painted every day for 14 days with 7-DHC (a cholesterol precursor; see Figure 6A), BM15766 (an inhibitor of cholesterol biosynthesis; see Figure 6B) or vehicle (ethanol or DMSO; see Figures 6A & 6B). The mice were then monitored for hair re-growth. Histological changes were monitored by H&E staining of paraffin-mounted mouse skin sections. At the end of 14 days, hair growth was fully restored in the vehicle-treated mice. Ethanol-treated mice are shown in Figure 6A and DMSO-treated mice in Figure 6B. In stark contrast, the hair follicles in mice treated with 7-DHC (Figure 6A) or BM15766 (Figure 6B) did not re-grow. We therefore determined whether BM15766 or 7-DHC had an effect on catagen induction or on hair follicle stem cells. As shown in Figure S2, real-time PCR showed that the expression of the TGFβ1 gene was significantly increased in mouse skin tissue after treatment with BM15766. In addition, the expression of SOX9 was significantly decreased both in HHFORS cells in culture and in mouse skin after treatment with 7-DHC and BM15766 (Figure S2).


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 inhibit hair growth and activate the inflammatory response in C57BL/6J mice.(A) Topical 7-DHC and (B) BM15766 treatment inhibited hair growth compared with vehicle treatment (ethanol or DMSO). Hair growth was restored in vehicle-treated but not in 7-DHC and BM15766 treated mice. (C, D) Histology of mouse skin treated with ethanol, DMSO, 7-DHC and BM15766 (20X). H&E staining of vehicle-treated mice showed normal hair follicles and sebaceous glands. In contrast, H&E staining of mice treated with 7-DHC and BM15766 showed hyperkeratosis as well as dystrophic hair follicles and sebaceous glands. Scale bar = 50 µm. (E, F) H&E staining showed peri-follicular and inter-follicular inflammation in mouse skin that had been treated with 7-DHC (40×). At higher magnification (100×), infiltration of tissue histiocytes is observed. (G, F) A higher percentage of F4/80 cells was present in mouse skin treated with 7-DHC (Q5-LR) and BM15766 (Q4-LR) than in the vehicle-treated mouse skin. See also Figures S3 and S4.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3369908&req=5

pone-0038449-g006: Sterol intermediates of cholesterol biosynthesis inhibit hair growth and activate the inflammatory response in C57BL/6J mice.(A) Topical 7-DHC and (B) BM15766 treatment inhibited hair growth compared with vehicle treatment (ethanol or DMSO). Hair growth was restored in vehicle-treated but not in 7-DHC and BM15766 treated mice. (C, D) Histology of mouse skin treated with ethanol, DMSO, 7-DHC and BM15766 (20X). H&E staining of vehicle-treated mice showed normal hair follicles and sebaceous glands. In contrast, H&E staining of mice treated with 7-DHC and BM15766 showed hyperkeratosis as well as dystrophic hair follicles and sebaceous glands. Scale bar = 50 µm. (E, F) H&E staining showed peri-follicular and inter-follicular inflammation in mouse skin that had been treated with 7-DHC (40×). At higher magnification (100×), infiltration of tissue histiocytes is observed. (G, F) A higher percentage of F4/80 cells was present in mouse skin treated with 7-DHC (Q5-LR) and BM15766 (Q4-LR) than in the vehicle-treated mouse skin. See also Figures S3 and S4.
Mentions: We next determined whether BM15766 and 7-DHC have the same effects on mouse skin in vivo (Figure 6). Mouse hair cycle stages are naturally synchronized in individual mice. However, animals of the same age and from the same litter can exhibit heterogeneity with respect to hair follicle cycling. Therefore, mice in the telogen phase of hair growth cycle (7 weeks old) were depilated to synchronize their hair cycle stages and painted every day for 14 days with 7-DHC (a cholesterol precursor; see Figure 6A), BM15766 (an inhibitor of cholesterol biosynthesis; see Figure 6B) or vehicle (ethanol or DMSO; see Figures 6A & 6B). The mice were then monitored for hair re-growth. Histological changes were monitored by H&E staining of paraffin-mounted mouse skin sections. At the end of 14 days, hair growth was fully restored in the vehicle-treated mice. Ethanol-treated mice are shown in Figure 6A and DMSO-treated mice in Figure 6B. In stark contrast, the hair follicles in mice treated with 7-DHC (Figure 6A) or BM15766 (Figure 6B) did not re-grow. We therefore determined whether BM15766 or 7-DHC had an effect on catagen induction or on hair follicle stem cells. As shown in Figure S2, real-time PCR showed that the expression of the TGFβ1 gene was significantly increased in mouse skin tissue after treatment with BM15766. In addition, the expression of SOX9 was significantly decreased both in HHFORS cells in culture and in mouse skin after treatment with 7-DHC and BM15766 (Figure S2).

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