Role of PXR in cutaneous homeostasis

Cutaneous homeostasis results from a tight control of keratinocyte proliferation-differentiation-apoptosis processes. Non-melanoma skin cancer originates from dysregulations of epidermal homeostasis as a result of malignant proliferation of keratinocytes eventually associated with alterations of the skin immune system. The nuclear hormone receptor pregnane X receptor (PXR) has mainly been studied in the liver and intestine where it is involved in the degradation of potentially harmful compounds. These substances derive from steroid and hormone metabolism but also from food and drugs. Recently, PXR was shown to regulate oxidative stress and to control cell proliferation. Preliminary studies from our laboratory show that PXR is expressed in skin and that its expression is higher in proliferating than in differentiating and apoptotic keratinocytes. Moreover, a PXR specific ligand induces epidermal hyperplasia in vivo in a PXR-dependent manner. Skin is in daily contact with potent PXR activators from the environment and from topical products but the long term effects of repeated PXR activation is unknown. The importance of PXR in mediating metabolic signalling and the association of PXR with cell proliferation led us to hypothesize that PXR plays a role in non-melanoma skin cancer development. In addition, we will explore the immuno-regulatory role of PXR in epidermal cancerogenesis. Insight into how PXR modulates various signalling pathways involved in these processes may unravel preventive strategies and the development of drugs that target this receptor.

Skin is in daily contact with potentially harmful molecules able to induce pathologies such as allergies, irritations and cancers. The molecular basis of skin response to such particles is poorly understood. The pregnane x receptor, PXR, has extensively been studied in the liver and intestine and has been shown to prevent accumulation of potentially deleterious compounds by promoting their transformation and elimination from the body. We are first to report expression of PXR in the skin and to investigate the role of PXR in immune cells. This discovery is very important because it opens a new research horizon that will help to better understand the impact that chemicals, drugs and pollutants can have on skin.Skin is one of the biggest organs of the body exhibiting high metabolic and catabolic properties. It is the interface between internal organs and our environment. Skin is therefore exposed to a broad range of challenges such as ultra-violet irradiations, chemicals, pollutants, allergens and microbes. Skin possesses defence strategies able to prevent excessive damage in response to all these insults. In this battery of protective biological stratagems, several proteins, able to regulate gene expression by binding to specific DNA sequences also called transcription factors, play a central role. These transcription factors are present in all cells in an inactivated or resting state until they encounter a molecule able to activate them. Environmental pollutants can penetrate the different layers of the skin and diffuse into cutaneous cells where they activate specific transcription factors. Then, cellular programs are initiated aiming to neutralize the harmful molecule and thus to prevent damages to cells such as structural degradation and DNA damage. Pollutants target irrespectively all skin cells including structural and metabolic cells as well as cells from the immune system.The pregnane x receptor, PXR, is a transcription factor central to drug, chemical and pollutant (also called xenobiotics) detoxification primarily found in the gastro-intestinal tract. Indeed, PXR is activated by a broad spectrum of molecules including antibiotics, anti-fungi, anti-cancer drugs, pesticides, endocrine disruptors and all kinds of pollutants contained in the atmosphere, cigarette smoke, cosmetics, shampoos and groundwater. PXR controls the expression of various enzymes able to transform dangerous lipo-soluble molecules into water-soluble compounds able to be eliminated from the body. Because our skin is in daily contact with harmful xenobiotics which are potential PXR activators, we aimed to explore the role of PXR in the skin and we were first to initiate such research program. Funding via the FWF helped us to delineate the role of PXR in the skin and in cells from the immune system. We found that PXR promotes DNA damage to epidermal cells after skin exposure to a single dose of pollutant and alters function of immune cells.