Impact of saturated fatty acid on endogenous retroelements reactivation during atopic dermatitis.

• Grant number: 25/05032-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: June 01, 2025
• End date: May 31, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Djalma de Souza Lima Júnior
• Grantee: Lucas Fernandes Alves da Silva
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 23/09270-2 - Decoding the role of endogenous retroviruses in controlling type 2 immunity, AP.JP

Abstract

Obesity and lipid-rich diets have been associated with an increase in the prevalence and severity of allergic diseases worldwide, such as asthma and atopic dermatitis. Recent findings suggest that an important factor contributing to this condition is related to the type of fatty acid consumed, rather than just the quantity. The Western diet, rich in saturated fatty acids such as palmitic acid and myristic acid, stimulates immune responses that promote the production of pro-inflammatory cytokines, intensifying inflammation. However, the impact of lipid consumption on skin inflammation is still poorly studied. Despite this, preliminary data showed that mice fed high-fat diets and supplemented orally with palmitic acid had an increase in the expression of endogenous retroviruses (ERVs) in the skin, as well as an increase in T cell accumulation and high keratinocyte proliferation, suggesting a link between lipid consumption and the reactivation of ERVs, which promotes an inflammatory response.Endogenous retroviruses are ancestral viral elements that, throughout evolution, have been integrated into the human genome and remain dormant under normal conditions. However, in situations of chronic inflammation or other environmental stimuli, these elements can be reactivated, increasing their expression. The reactivation of ERVs has been associated with the modulation of immune responses and plays a crucial role in the pathogenesis of various diseases, including autoimmune disorders, cancer, and skin inflammatory conditions. ERV reactivation can contribute to the activation of immune cells and the production of pro-inflammatory cytokines, exacerbating inflammatory processes and worsening immune-related diseases. However, little is known about the role of ERVs in allergic inflammation, as well as their contribution to the exacerbation of these inflammatory processes in the context of a high fat diet.The aim of this project is to investigate how a diet rich in saturated fatty acids, specifically palmitic and myristic acids, influences the reactivation of ERVs and immune responses associated with skin inflammation in the context of atopic dermatitis. To do this, we will evaluate the effect of these fatty acids on ERV expression by stimulating primary mouse and human keratinocyte cell lines with these fatty acids, assessing ERV reactivation through flow cytometry and qRT-PCR, as well as the consistency of these effects in three-dimensional (3D) human skin models. Next, we will characterize the ERV expression profile in mice fed a diet enriched with palmitic acid. Afterward, we will apply an ointment containing Dermatophagoides farinae (HDM) extract to induce atopic dermatitis, using flow cytometry and qRT-PCR to analyze ERV expression. Finally, we will investigate how ERV activation influences the immune response in atopic dermatitis in the context of a palmitic acid-rich diet. For this, we will use antiretroviral cocktails to inhibit reverse transcription in mice with atopic dermatitis on this diet. Subsequently, through immunological assays, we will analyze cytokine profiles, immune cell composition and activation, as well as gene expression. We believe this project will lead to significant advances in understanding the factors that regulate tissue immunity and inflammation, while also highlighting the potential risks of excessive consumption of lipid-rich diets-whether through food or supplements-in the development of skin disorders. (AU)