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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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Innate immune genes are upregulated in PCA.Real-time PCR validation of (A) TLR4, (B) TLR6, (C) IFNα, (D) IFNα7, (E) NFkB, (F) IFNγ, (G) MMD and (H) MCP1 in mixed (DC, DF), neutrophilic (TF, FD) and lymphocytic (FFA, LPP, CCCA) PCA. These genes are significantly upregulated in affected tissue compared to unaffected tissue from the same patients (*p<0.05, **p<0.01). The unpaired t-test was used for statistical analysis. Differences in the pattern of expression of these genes were observed in the different PCA subtypes. (I) IPA identified the interferon signaling pathway or the “interferon-responsive signature” in the gene expression profiles of LPP. The intensity of the node color red indicates the degree of upregulation, and the intensity of the color green indicates the degree of downregulation. Genes shown as uncolored nodes were not identified as differentially expressed in our experiment and were integrated into the computationally generated networks based on the evidence stored in the IPA knowledge base, which indicated a relevance to this network. The node shapes denote enzymes, phosphatases, kinases, peptidases, transmembrane receptors, cytokines, transporters, translation factors, nuclear receptors and transcription factors. The interferon target genes IRF1, IRF8, IFNA5, IFNAR2, IFIT3, IFITM1, MX1, OAS1 and IFI35 are significantly upregulated in LPP. See also Table S2.
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pone-0038449-g004: Innate immune genes are upregulated in PCA.Real-time PCR validation of (A) TLR4, (B) TLR6, (C) IFNα, (D) IFNα7, (E) NFkB, (F) IFNγ, (G) MMD and (H) MCP1 in mixed (DC, DF), neutrophilic (TF, FD) and lymphocytic (FFA, LPP, CCCA) PCA. These genes are significantly upregulated in affected tissue compared to unaffected tissue from the same patients (*p<0.05, **p<0.01). The unpaired t-test was used for statistical analysis. Differences in the pattern of expression of these genes were observed in the different PCA subtypes. (I) IPA identified the interferon signaling pathway or the “interferon-responsive signature” in the gene expression profiles of LPP. The intensity of the node color red indicates the degree of upregulation, and the intensity of the color green indicates the degree of downregulation. Genes shown as uncolored nodes were not identified as differentially expressed in our experiment and were integrated into the computationally generated networks based on the evidence stored in the IPA knowledge base, which indicated a relevance to this network. The node shapes denote enzymes, phosphatases, kinases, peptidases, transmembrane receptors, cytokines, transporters, translation factors, nuclear receptors and transcription factors. The interferon target genes IRF1, IRF8, IFNA5, IFNAR2, IFIT3, IFITM1, MX1, OAS1 and IFI35 are significantly upregulated in LPP. See also Table S2.

Mentions: The predominantly upregulated inflammatory genes in PCA are shown as a heat map (Figure 3I). Various genes were identified in the “immune cluster,” including genes whose products control the innate immune responses, such as the interleukin/Toll-like receptor superfamily, interferon inducible proteins, and monocyte/macrophage related proteins. Genes whose products are required for the adaptive immune response, such as chemokine/cytokine family members, T and B cell activation and survival genes, genes encoding MAP kinases, members of the tumor necrosis factor superfamily and the major histocompatibility complex class I and class II genes, were also overexpressed in PCA. The microarray data were validated by performing real-time PCR for TLR4, TLR6, IFNα, IFNα7, NFkB and IFNγ in tissues from patients with lymphocytic and neutrophilic PCA. As shown in Figure 4A–4H, real-time PCR with target-gene-specific primers confirmed that Toll-like receptor (TLR4, TLR6), interferon (IFNα, IFNα7, IFNγ), pro-inflammatory cytokine (NFkB) and macrophage activation factor (MMD, MCP1) genes are all significantly upregulated in affected PCA tissue compared with unaffected tissue from the same patients.


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)

Innate immune genes are upregulated in PCA.Real-time PCR validation of (A) TLR4, (B) TLR6, (C) IFNα, (D) IFNα7, (E) NFkB, (F) IFNγ, (G) MMD and (H) MCP1 in mixed (DC, DF), neutrophilic (TF, FD) and lymphocytic (FFA, LPP, CCCA) PCA. These genes are significantly upregulated in affected tissue compared to unaffected tissue from the same patients (*p<0.05, **p<0.01). The unpaired t-test was used for statistical analysis. Differences in the pattern of expression of these genes were observed in the different PCA subtypes. (I) IPA identified the interferon signaling pathway or the “interferon-responsive signature” in the gene expression profiles of LPP. The intensity of the node color red indicates the degree of upregulation, and the intensity of the color green indicates the degree of downregulation. Genes shown as uncolored nodes were not identified as differentially expressed in our experiment and were integrated into the computationally generated networks based on the evidence stored in the IPA knowledge base, which indicated a relevance to this network. The node shapes denote enzymes, phosphatases, kinases, peptidases, transmembrane receptors, cytokines, transporters, translation factors, nuclear receptors and transcription factors. The interferon target genes IRF1, IRF8, IFNA5, IFNAR2, IFIT3, IFITM1, MX1, OAS1 and IFI35 are significantly upregulated in LPP. See also Table S2.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3369908&req=5

pone-0038449-g004: Innate immune genes are upregulated in PCA.Real-time PCR validation of (A) TLR4, (B) TLR6, (C) IFNα, (D) IFNα7, (E) NFkB, (F) IFNγ, (G) MMD and (H) MCP1 in mixed (DC, DF), neutrophilic (TF, FD) and lymphocytic (FFA, LPP, CCCA) PCA. These genes are significantly upregulated in affected tissue compared to unaffected tissue from the same patients (*p<0.05, **p<0.01). The unpaired t-test was used for statistical analysis. Differences in the pattern of expression of these genes were observed in the different PCA subtypes. (I) IPA identified the interferon signaling pathway or the “interferon-responsive signature” in the gene expression profiles of LPP. The intensity of the node color red indicates the degree of upregulation, and the intensity of the color green indicates the degree of downregulation. Genes shown as uncolored nodes were not identified as differentially expressed in our experiment and were integrated into the computationally generated networks based on the evidence stored in the IPA knowledge base, which indicated a relevance to this network. The node shapes denote enzymes, phosphatases, kinases, peptidases, transmembrane receptors, cytokines, transporters, translation factors, nuclear receptors and transcription factors. The interferon target genes IRF1, IRF8, IFNA5, IFNAR2, IFIT3, IFITM1, MX1, OAS1 and IFI35 are significantly upregulated in LPP. See also Table S2.
Mentions: The predominantly upregulated inflammatory genes in PCA are shown as a heat map (Figure 3I). Various genes were identified in the “immune cluster,” including genes whose products control the innate immune responses, such as the interleukin/Toll-like receptor superfamily, interferon inducible proteins, and monocyte/macrophage related proteins. Genes whose products are required for the adaptive immune response, such as chemokine/cytokine family members, T and B cell activation and survival genes, genes encoding MAP kinases, members of the tumor necrosis factor superfamily and the major histocompatibility complex class I and class II genes, were also overexpressed in PCA. The microarray data were validated by performing real-time PCR for TLR4, TLR6, IFNα, IFNα7, NFkB and IFNγ in tissues from patients with lymphocytic and neutrophilic PCA. As shown in Figure 4A–4H, real-time PCR with target-gene-specific primers confirmed that Toll-like receptor (TLR4, TLR6), interferon (IFNα, IFNα7, IFNγ), pro-inflammatory cytokine (NFkB) and macrophage activation factor (MMD, MCP1) genes are all significantly upregulated in affected PCA tissue compared with unaffected tissue from the same patients.

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