Psoriasis is a cutaneous autoimmune disease that affects approximately 2% of the population and has no cure. It is a cell-mediated disease in which NF-B-regulated cytokine expression and the IL-23/IL-17 axis are key susceptibility pathways involved in pathogenesis. Thus, therapeutics targeting these pathways would be highly advantageous. Naturally occurring electrophilic nitro-fatty acids, such as nitro-oleic acid (OA-NO2), are nitration products of unsaturated fatty acids that mediate anti-inflammatory, antioxidant, and cytoprotective reactions. The therapeutic potential of nitro-fatty acids has been demonstrated in several in vivo murine models of inflammatory disease. In this regard, OA-NO2 inhibits NF-?B signal transduction, thereby suppressing pro- inflammatory responses and distinguishing psoriasis as an excellent candidate for electrophilic nitro-fatty acid therapies. Ongoing studies demonstrate that subcutaneous (SC) injections of OA-NO2 inhibit and treat contact hypersensitivity (CHS) in a murine model. Thus, we hypothesize that targeting the skin immune system with electrophilic fatty acids will suppress cutaneous inflammatory processes central to psoriasis. The studies we propose will identify and distinguish the mechanisms involved in inducing the cutaneous anti- inflammatory immune response observed following SC injections of electrophilic fatty acids in inflammatory skin diseases. The goal of this preclinical proposal is to enable translational application of this new class of drugs for the treatment of psoriasis and other inflammatory skin diseases by examining the specific aims:
Aim 1. Define the protective mechanisms induced by OA-NO2 in a murine model of ACD.
Aim 2. Determine the anti-inflammatory effects of OA-NO2 on psoriasis. The conserved nature of electrophilic fatty acids supports the translational value of the preclinical studies we propose and provide an opportunity to utilize a unique and innovative approach by combing both human and murine inflammatory models, including the humanized mouse xenograft model and the K14-VEGF murine model. These studies will identify the mechanisms underlying the anti-inflammatory and protective effects of electrophilic fatty acids in the skin. They will reveal endogenous lipid signaling mechanisms in the skin and will improve our understanding of the function of electrophilic NO2-FA in skin immunity. Finally, these studies will inform the therapeutic development of electrophilic nitro-fatty acids for the treatment of skin diseases.
To date there is a variety of topical and systemic treatments for use in psoriatic patients; however, these treatments are not effective in all patients, relapse tend to occur, and less than 40% of patients are satisfied with their current therapies. Additionally, therapeutics for psoriasis include the use of systemic acting immuno- suppressive drugs; which, the immuno-suppression and long-term adverse effects can lead to infections and cancer. Thus, the goal of this proposal is to determine if the highly beneficial health effects of electrophilic fatty acids can be safely translated into therapeutics for psoriasis and other cutaneous inflammatory diseases.
| Mathers, Alicia R; Carey, Cara D; Killeen, Meaghan E et al. (2018) Topical electrophilic nitro-fatty acids potentiate cutaneous inflammation. Free Radic Biol Med 115:31-42 |
| Mathers, A R; Carey, C D; Killeen, M E et al. (2017) Electrophilic nitro-fatty acids suppress allergic contact dermatitis in mice. Allergy 72:656-664 |
| Monin, Leticia; Gudjonsson, Johann E; Childs, Erin E et al. (2017) MCPIP1/Regnase-1 Restricts IL-17A- and IL-17C-Dependent Skin Inflammation. J Immunol 198:767-775 |
