Grant Abstract: Impact of dietary lipid components on phototherapy used to treat inflammatory skin conditions

Grant Number: 1R01AR084311-01A1
PI Name: Schopfer
Project Title: Impact of dietary lipid components on phototherapy used to treat inflammatory skin conditions

Abstract: The skin serves as a vital barrier against external factors such as pathogens, environmental threats, and water loss. Diet plays a significant role in maintaining barrier integrity and function, a critical activity for overall health. Lipids composed of fatty acids are fundamental constituents of the skin. Moreover, skin exhibits heightened sensitivity to fatty acid deficiency, and fatty acids play a pivotal role in skin immune and inflammatory responses. Reactions between nitric oxide (NO), nitrite (NO2-), and unsaturated fatty acids that occur during inflammatory processes give rise to electrophilic nitro-fatty acids (NO2-FAs) such as conjugated nitro linoleic acid (NO2-CLA). Importantly, NO2-FAs exhibit potent anti-inflammatory and cytoprotective properties as an inherent mechanism to control inflammation. Thus, NO2-FAs emerge as critical signaling mediators in response to inflammation, playing a pivotal role in reducing inflammation and safeguarding tissues. The anti-inflammatory effects of therapeutically dosed NO2-FAs are evident across diverse disease conditions, including psoriasis, an autoimmune skin disease affecting 2% of the US population and dependent on the IL-23/IL-17 cytokine axis. In this regard, oral administration of NO2-FAs has proven highly effective in treating mouse models of psoriasis, and importantly, our recent findings indicate that commonly employed UV phototherapy for psoriasis treatments induces specific NO2-CLA formation in the skin through direct photoreactions. In humans, CLA is an essential fatty acid only obtained through diet, and thus, the formation of NO2-CLA depends on the diet, which can be significantly enhanced through nutritional supplementation. Importantly, phototherapy can be combined with other medications to treat severe recalcitrant psoriatic lesions. We hypothesize that dietary supplementation of CLA will increase its cutaneous levels and play a therapeutic role in psoriasis treatment through the phototherapy-induced formation of NO2-CLA. This will provide new nutritional approaches to alleviate autoimmune and inflammatory diseases. Thus, the goal of this proposal is to define dietary CLA as a key component that enhances NO2-CLA formation in the skin to moderate exacerbated autoimmune responses. To test the central hypothesis, the following Specific Aims will be pursued: Aim 1: Define the impact of dietary CLA on NO2-CLA formation in skin tissues. Aim 2: Establish the protective effects of endogenous NO2-CLA formation on psoriasis. Aim 3: Determine the molecular and cellular protective mechanisms of endogenous NO2-CLA in psoriasis. This proposed Research Plan will provide quantitative insight into new properties of CLA modulating inflammation in the skin through the formation of NO2-CLA. The research team members are uniquely positioned to achieve the significant objective of devising intervention strategies to promote fatty acid nitration to impact signaling responses that limit the inflammatory processes in the skin. PUBLIC HEALTH RELEVANCE: Dietary interventions with conjugated linoleic acid have a positive impact on inflammatory and immune diseases, increase the levels of nitrated fatty acids, and have shown benefits in animal models of psoriasis. We recently found that nitrated fatty acids are highly protective against psoriasis and are formed during phototherapy, a commonly used treatment for the disease. Our goal is to define how dietary interventions with conjugated linoleic acid promote anti-inflammatory and protective actions in psoriasis by forming nitrated fatty acids.

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