Lipid-Metabolic Regulation of Allergic Skin Inflammation

Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Immunobiology

First Advisor

Flavell, Richard

Abstract

Maintenance of barrier tissues during disturbances to homeostasis requires the coordination of immune and epithelial cell responses. Much of our knowledge of this coordination is rooted in the roles of proteins like cytokines in facilitating intercellular communication. However, it is now well appreciated that metabolites have a profound ability to shape immune cell responses, yet the way in which metabolites shape immune epithelial crosstalk in barrier tissues remains understudied. Previous studies identified elevated Fatty Acid Binding Protein 5 (FABP5) in the skin and circulation as a potential biomarker for atopic dermatitis; however, it is unclear whether FABP5 regulates lipid metabolism or modulates epidermal or immune cell function during disease. These observations led us to hypothesize that FABP5 may function as a critical regulatory node, facilitating immune-epithelial communication by modulating lipid metabolism during disease. Using a murine model of atopic dermatitis, we found that FABP5 is highly expressed in both keratinocytes and skin-resident immune cells, and that FABP5 deficiency leads to exacerbated skin inflammation characterized by increased vascular leak and neutrophil infiltration. Lipidomic analysis revealed that FABP5 deficiency disrupts the metabolism of ether-linked lipids, which are essential precursors for the synthesis of the potent inflammatory mediator platelet activating factor (PAF). Concordantly, we observed that FABP5-deficient mice had elevated concentrations of PAF in skin and circulation, and that depletion of basophils, a major source of PAF, rescued exacerbated skin inflammation observed in FABP5-deficient mice. Altogether, the research detailed in this dissertation reveals a novel role for FABP5 in regulating ether-lipid metabolism during allergic inflammation and enhances our understanding of how lipid metabolic pathways influence immune function in barrier tissues.

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