Sterol Intermediates of Cholesterol Biosynthesis Inhibit Hair Growth and Trigger an Innate Immune Response in Cicatricial Alopecia

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

Evaluating the association of central centrifugal cicatricial alopecia (CCCA) and fibroproliferative disorders

Background: In central centrifugal cicatricial alopecia (CCCA), a lymphocytic scarring alopecia that primarily affects black women, it has been postulated that there is a "pro-fibrotic" tendency and increased risk for systemic fibroproliferative disorders. Objective: To determine whether women with biopsy-proven CCCA have a greater likelihood of systemic fibroproliferative disorders (FPDs) of the lungs (interstitial lung disease), arteries (atherosclerosis of the aorta), liver (non-alcoholic steatohepatitis), kidney (end stage renal disease), or uterus (uterine leiomyoma). Methods: We conducted a retrospective matched cohort study evaluating 427 cases with biopsy-proven CCCA and 1281 age- and sex-matched controls. Results: Black women with biopsy-proven CCCA, were not more likely to have interstitial lung disease (ILD), atherosclerosis of the aorta, non-alcoholic steatohepatitis (NASH), end stage renal disease (ESRD), or uterine leiomyoma. Central centrifugal cicatricial alopecia was associated with a history of never smoking and higher body mass index. Conclusion: In this large cohort of biopsy-proven women with CCCA, there was no association with specific fibroproliferative disorders when compared with age and sex matched controls. Future longitudinal studies may help confirm these results

Protein profiling of forehead epidermal corneocytes distinguishes frontal fibrosing from androgenetic alopecia.

Protein profiling offers an effective approach to characterizing how far epidermis departs from normal in disease states. The present pilot investigation tested the hypothesis that protein expression in epidermal corneocytes is perturbed in the forehead of subjects exhibiting frontal fibrosing alopecia. To this end, samples were collected by tape stripping from subjects diagnosed with this condition and compared to those from asymptomatic control subjects and from those exhibiting androgenetic alopecia. Unlike the latter, which exhibited only 3 proteins significantly different from controls in expression level, forehead samples from frontal fibrosing alopecia subjects displayed 72 proteins significantly different from controls, nearly two-thirds having lower expression. The results demonstrate frontal fibrosing alopecia exhibits altered corneocyte protein expression in epidermis beyond the scalp, indicative of a systemic condition. They also provide a basis for quantitative measures of departure from normal by assaying forehead epidermis, useful in monitoring response to treatment while avoiding invasive biopsy

Protein profiling of forehead epidermal corneocytes distinguishes frontal fibrosing from androgenetic alopecia.

Protein profiling offers an effective approach to characterizing how far epidermis departs from normal in disease states. The present pilot investigation tested the hypothesis that protein expression in epidermal corneocytes is perturbed in the forehead of subjects exhibiting frontal fibrosing alopecia. To this end, samples were collected by tape stripping from subjects diagnosed with this condition and compared to those from asymptomatic control subjects and from those exhibiting androgenetic alopecia. Unlike the latter, which exhibited only 3 proteins significantly different from controls in expression level, forehead samples from frontal fibrosing alopecia subjects displayed 72 proteins significantly different from controls, nearly two-thirds having lower expression. The results demonstrate frontal fibrosing alopecia exhibits altered corneocyte protein expression in epidermis beyond the scalp, indicative of a systemic condition. They also provide a basis for quantitative measures of departure from normal by assaying forehead epidermis, useful in monitoring response to treatment while avoiding invasive biopsy

Development of a Surrogate Autonomous Aircraft for Entry in the NASA Airspace Operation Challenge

The integration of UAS into the National Airspace, although imminent, still presents several technological challenges. Before a sucessful integration can occur, it is necessary to demonstrate different technologies in traffic detection, traffic avoidance, and communications, as well as in the integration of those technologies as a single unit. For this purpose, NASA developed its UAS Airspace Operation Challenge; a Centennial Challenge aimed at the demonstration of these technologies. The challenge consists of developing a UAS solution that can navigate autonomously while detecting and avoiding traffic using ADS-B signals. Embry-Riddle Aeronautical Univeristy developed an entry to this challenge: a UAS consisting of a surrogate UAV, a ground station, and a data link. The traffic detection challenges are addressed by processing images collected from an array of cameras mounted in the wingtips, while the avoidance challenges are addressed with a series of path planning algorithms. For communication, a ground station was built and equipped with a data link for monitoring the aircraft’s systems. The individual components were tested sucessfully, but flight test of the integrated unit is still in progress. The challenge was cancelled, but Embry-Riddle’s entry remains a valuable asset for UAS integration technology

Ingenuity pathway analysis.

Submission of data from the comparison of FFA with control forehead profiles resulted in identification of two pathways that appeared suppressed, both containing PLCD1 and three 14-3-3 adaptor proteins (SFN, YWHAZ, YWHAE). (PDF)</p

Inflammatory pathways and networks activated in C57BL/6J mouse skin after topical treatment with 7-DHC and BM15766.

<p>(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 <i>TLR4</i> and <i>IFN</i> 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 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038449#pone.0038449.s008" target="_blank">Table S4</a>. Real-time PCR validation of (E) <i>TLR4</i>, (F) <i>TLR6</i>, (G) <i>IFNα</i>, (H) <i>IFNα7</i>, (I) <i>NFkB</i>, (J) <i>IFNγ,</i> (K) <i>MMD</i> and (L) <i>MCP1</i> 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 <i>t-</i>test was used for the statistical analysis. Treatment with 7-DHC and BM15766 can induce the expression of some or all of these genes.</p