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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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Inflammatory pathways and networks activated in C57BL/6J mouse skin after topical treatment with 7-DHC and BM15766.(A) The most significant signaling pathways altered by 7-DHC treatment participated in the inflammatory and immune responses and were identified using IPA. Fisher’s exact test was used to calculate p values to determine the probability that the association between the genes in the dataset and the pathway could be explained by chance alone. The yellow line indicates the threshold of significance (p<0.05) and represents the ratio of the number of molecules from the data set that map to the pathway to the total number of molecules that map to the pathway. (B) The top differentially regulated pathways in BM15766-treated mouse skin. The majority of the upregulated pathways participated in the inflammatory and immune responses. (C, D) The top two predicted networks in 7DHC-treated mouse skin, determined using IPA. The TLR4 and IFN gene networks are significantly upregulated by 7-DHC. Solid lines denote direct relationships between genes. Dotted lines denote an indirect relationship between two genes. A red node denotes an upregulated gene, and a green node denotes a downregulated gene. See also Table S4. Real-time PCR validation of (E) TLR4, (F) TLR6, (G) IFNα, (H) IFNα7, (I) NFkB, (J) IFNγ, (K) MMD and (L) MCP1 gene expression in mouse skin treated with 7-DHC or BM15766 compared with vehicle-treated (ethanol or DMSO) controls (n = 3; *p<0.05, **p<0.01). The unpaired t-test was used for the statistical analysis. Treatment with 7-DHC and BM15766 can induce the expression of some or all of these genes.
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pone-0038449-g007: Inflammatory pathways and networks activated in C57BL/6J mouse skin after topical treatment with 7-DHC and BM15766.(A) The most significant signaling pathways altered by 7-DHC treatment participated in the inflammatory and immune responses and were identified using IPA. Fisher’s exact test was used to calculate p values to determine the probability that the association between the genes in the dataset and the pathway could be explained by chance alone. The yellow line indicates the threshold of significance (p<0.05) and represents the ratio of the number of molecules from the data set that map to the pathway to the total number of molecules that map to the pathway. (B) The top differentially regulated pathways in BM15766-treated mouse skin. The majority of the upregulated pathways participated in the inflammatory and immune responses. (C, D) The top two predicted networks in 7DHC-treated mouse skin, determined using IPA. The TLR4 and IFN gene networks are significantly upregulated by 7-DHC. Solid lines denote direct relationships between genes. Dotted lines denote an indirect relationship between two genes. A red node denotes an upregulated gene, and a green node denotes a downregulated gene. See also Table S4. Real-time PCR validation of (E) TLR4, (F) TLR6, (G) IFNα, (H) IFNα7, (I) NFkB, (J) IFNγ, (K) MMD and (L) MCP1 gene expression in mouse skin treated with 7-DHC or BM15766 compared with vehicle-treated (ethanol or DMSO) controls (n = 3; *p<0.05, **p<0.01). The unpaired t-test was used for the statistical analysis. Treatment with 7-DHC and BM15766 can induce the expression of some or all of these genes.

Mentions: To elucidate the mechanisms and signaling pathways underlying our findings, we performed gene expression profiling and IPA analysis to compare mouse skin that had been treated with 7-DHC and BM15766 with untreated controls. The inflammatory and immune pathways that were upregulated in 7-DHC-treated mouse skin included acute phase response signaling, SLE signaling, dendritic cell maturation and interferon signaling (Figure 7A). Pathways that were upregulated in BM15766-treated mouse skin included IL-10 signaling, T- and B-cell signaling in RA, IL-6 signaling and dendritic cell maturation (Figure 7B). As observed in vitro, we identified upregulation of TLR (Figure 7C, Table S4) and interferon signaling networks (Figure 7D, Table S4) in 7-DHC - treated mouse skin.


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)

Inflammatory pathways and networks activated in C57BL/6J mouse skin after topical treatment with 7-DHC and BM15766.(A) The most significant signaling pathways altered by 7-DHC treatment participated in the inflammatory and immune responses and were identified using IPA. Fisher’s exact test was used to calculate p values to determine the probability that the association between the genes in the dataset and the pathway could be explained by chance alone. The yellow line indicates the threshold of significance (p<0.05) and represents the ratio of the number of molecules from the data set that map to the pathway to the total number of molecules that map to the pathway. (B) The top differentially regulated pathways in BM15766-treated mouse skin. The majority of the upregulated pathways participated in the inflammatory and immune responses. (C, D) The top two predicted networks in 7DHC-treated mouse skin, determined using IPA. The TLR4 and IFN gene networks are significantly upregulated by 7-DHC. Solid lines denote direct relationships between genes. Dotted lines denote an indirect relationship between two genes. A red node denotes an upregulated gene, and a green node denotes a downregulated gene. See also Table S4. Real-time PCR validation of (E) TLR4, (F) TLR6, (G) IFNα, (H) IFNα7, (I) NFkB, (J) IFNγ, (K) MMD and (L) MCP1 gene expression in mouse skin treated with 7-DHC or BM15766 compared with vehicle-treated (ethanol or DMSO) controls (n = 3; *p<0.05, **p<0.01). The unpaired t-test was used for the statistical analysis. Treatment with 7-DHC and BM15766 can induce the expression of some or all of these genes.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3369908&req=5

pone-0038449-g007: Inflammatory pathways and networks activated in C57BL/6J mouse skin after topical treatment with 7-DHC and BM15766.(A) The most significant signaling pathways altered by 7-DHC treatment participated in the inflammatory and immune responses and were identified using IPA. Fisher’s exact test was used to calculate p values to determine the probability that the association between the genes in the dataset and the pathway could be explained by chance alone. The yellow line indicates the threshold of significance (p<0.05) and represents the ratio of the number of molecules from the data set that map to the pathway to the total number of molecules that map to the pathway. (B) The top differentially regulated pathways in BM15766-treated mouse skin. The majority of the upregulated pathways participated in the inflammatory and immune responses. (C, D) The top two predicted networks in 7DHC-treated mouse skin, determined using IPA. The TLR4 and IFN gene networks are significantly upregulated by 7-DHC. Solid lines denote direct relationships between genes. Dotted lines denote an indirect relationship between two genes. A red node denotes an upregulated gene, and a green node denotes a downregulated gene. See also Table S4. Real-time PCR validation of (E) TLR4, (F) TLR6, (G) IFNα, (H) IFNα7, (I) NFkB, (J) IFNγ, (K) MMD and (L) MCP1 gene expression in mouse skin treated with 7-DHC or BM15766 compared with vehicle-treated (ethanol or DMSO) controls (n = 3; *p<0.05, **p<0.01). The unpaired t-test was used for the statistical analysis. Treatment with 7-DHC and BM15766 can induce the expression of some or all of these genes.
Mentions: To elucidate the mechanisms and signaling pathways underlying our findings, we performed gene expression profiling and IPA analysis to compare mouse skin that had been treated with 7-DHC and BM15766 with untreated controls. The inflammatory and immune pathways that were upregulated in 7-DHC-treated mouse skin included acute phase response signaling, SLE signaling, dendritic cell maturation and interferon signaling (Figure 7A). Pathways that were upregulated in BM15766-treated mouse skin included IL-10 signaling, T- and B-cell signaling in RA, IL-6 signaling and dendritic cell maturation (Figure 7B). As observed in vitro, we identified upregulation of TLR (Figure 7C, Table S4) and interferon signaling networks (Figure 7D, Table S4) in 7-DHC - treated mouse skin.

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