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Scavenger receptor B1 (SRB1), is a membrane receptor involved in several physiological functions including cholesterol and lipid soluble vitamins uptake, pathogens recognition and vesicles trafficking. Although this receptor is mainly localized in the liver and steroidogenic tissues, it has been shown to be expressed also in human skin. Recent studies have evidenced SRB1 susceptibility to oxidative stress and considering that cutaneous tissue is the main organ exposed to the outdoor stressors, it was our interest to understand whether the exposure of skin to environmental pollutants could affect its expression and consequently skin physiology. To answer our questions, we have performed experiments with homemade 3D skin models exposed to different pollutants: ozone, PM and cigarette smoke. Surprisingly all the stressors were able to down-regulate SRB1. In addition, the loss of SRB1 (after the challenges or by siRNA) prevented tissue wound closure and proliferation. Moreover, by the use of SR-B1 knockdown organotypic skin model, we showed a striking change in lipids organization within the epidermis. Our findings suggest that SR-B1 loss upon outdoor insults may influence cutaneous repair and lipid homeostasis making it as a key player in maintaining skin homeostasis.

The modulation of the HDL receptor scavenger receptor B1 (SRB1) was evaluated in skin fibroblasts isolated from Rett syndrome (RTT) patients, a rare neurodevelopmental disorder affecting almost exclusively females associated in up to 95% of cases to de novo loss-of-function mutations in the X-chromosome-linked gene encoding the methyl-CpG-binding protein 2 (MeCP2). Patients showed an altered plasma lipid profile, while their skin fibroblasts showed a dramatic reduction in SRB1 (immunogold, Western blot and immunohistochemistry). The decreased SRB1 levels were demonstrated to be the consequence of its binding with 4-hydroxy-2-nonenal (4HNE), a product of lipid peroxidation, and its increased ubiquitination. Therefore the loss of SRB1 in RTT cells is a consequence of the chronic oxidative stress status present in RTT. In addition RTT fibroblast presented high intracellular levels of H2O2 and 4HNE protein adducts. This finding was correlated with the constitutive activation of NADPH oxidase (NOX) and was reverted by DPI (NOX inhibitor) or Desferal (Iron chelator) pre-treatment. To confirm the alteration of status redox in RTT cells, the activity of several enzymes involved in protecting the cell from OS was also evaluated. Glutathione peroxidase (GPx), Supeoxide dismutase and Glucose-6-phosphate dehydrogenase (G6PDH) activity were decreased respect to control. These data paralleled with a constitutive activation of NRF2 and elevated gene expression of Heme oxigenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 (NQO-1). Of note, when NRF2 pathway was stimulated via exogenous oxidants, RTT fibroblast did not respond as the control cells.