Pleiotropic role of TRPV1 in inflammation in psoriasis – TRIP

Mammalian skin is an organ containing multiple tissues (epidermis, dermis, hypodermis), multiple cellular types (keratinocytes, fibroblasts, endothelial, muscle, and immune cells but also peripheral nerve fibres) and appendages that are in permanent communication in physiologic and pathological conditions. The maintenance of skin homeostasis relies on a finely tuned equilibrium of well-regulated interactions between its different components through which peripheral nervous system is strongly involved. Dysregulation of this equilibrium contributes to the pathogenesis of inflammatory skin diseases such as psoriasis, a frequent illness that affects 1-3% of the French population. Although substantial advances have been made to elucidate the role of immune-driven inflammation in psoriasis, the contribution of the nervous system remains poorly understood, with contradictory results. Especially, the regulation of vascular inflammation by peripheral nerves and participation of keratinocytes has been scarcely investigated and remains unclear. Widely expressed in skin sensory nerve endings, transient receptor potential vanilloid receptor subtype 1 (TRPV1) has a prominent role in pain sensation and inflammation. However, TRPV1 expression is not restricted to neuronal cells. It is also expressed by epidermal keratinocytes and cutaneous microvessels, which are associated with multiple cellular interactions and regulations in the skin, including inflammatory process. We thus hypothesize that the TRPV1 receptors on non-neuronal cells and neuronal cells could be involved in the vicious circle inflammation process in psoriasis. Putting TRPV1 at the centre of the dysregulation of homeostatic equilibrium including epithelial, neuronal and vascular inflammation in psoriasis is a totally innovative hypothesis. Our first objective is to demonstrate the central role of TRPV1 in the pathogenesis of psoriasis. In this context, we will identify the role of TRPV1 and which of the cells that express TRPV1 play a key role in the inflammatory vicious circle. Our second objective is to study the implication of microvasculature which is poorly studied in the context of psoriasis. Our last objective is to understand the different cellular communications between cellular types (neurons, basal and differentiated keratinocytes, and endothelial cells) in regards of neuropeptides, cytokines and TRPV1 activation. This project is organized in 3 workpackages with 3 partners. It aims at deciphering the pleiotropic role of TRPV1 in the inflammation in psoriasis with a particular interest on endothelium, keratinocytes and nerve interactions. To reach these ambitious goals, the TRIP project will apply a multidisciplinary approach, combining in vivo neurovascular evaluation expertise from the Partner3 (P3), clinical expertise from partner Partner1 (P1), ex vivo analysis of skin biopsies (psoriatic patients and experimental mouse models) from partners P1, P2, P3, and expertise for in vitro experiments with cellular cultures and co-cultures from partners P1 and P2. Large array analysis of proteins and transcript coupled with functionality tests using healthy, psoriatic and inflammatory in vivo, ex vivo and in vitro models is totally ground-breaking to study TRPV1 central role in psoriasis. Furthermore, these studies significantly increase knowledge in vascular inflammation regulation by local sensory nerves in psoriasis that is poorly studied. This project possess a high potential of industrial valorisation but also of diffusion towards scientific community and societal. Partners aim to implements a base to develop a highly strong network in the field and disseminate new young scientist for the international community.