PFOA targets B cell lipid raft organization and function

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PROJECT SUMMARY Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic organic chemicals that are widely used in consumer products. Given their chemical stability, PFAS are highly persistent in the environment and are detected in the water supply, food products, soil, and plants/animals. PFAS can exert immunotoxic effects. Notably, there is evidence that the legacy PFAS known as perfluorooctanoic acid (PFOA) can impair humoral immunity, the arm of the immune system that drives antibody production from B cells. A major limitation in the field is that underlying targets and mechanisms by which PFOA dysregulates humoral immunity are unknown. Therefore, the objective of this application is to explore new cellular and molecular mechanistic targets of PFOA. One novel target of PFOA is B cell lipid rafts. Lipid rafts are tightly packed regions of the plasma membrane made of sphingolipids/phospholipids and cholesterol that serve as platforms for membrane proteins to efficiently transmit downstream signals. Plasma membrane lipid rafts have a critical role in controlling B cell activation. Thus, understanding how PFOA exposure leads to dysregulated B cell lipid raft formation would provide a new mechanistic target by which this compound induces immunotoxicity. Herein, we propose the central hypothesis that PFOA increases the abundance of unstable plasma membrane lipid rafts of naïve B cells. Mechanistically, this is driven by PFOA incorporating into lipid rafts and thereby driving lipid raft- associated lipids into non-raft regions of the plasma membrane. As a consequence, PFOA creates an impediment toward effective localization of signaling receptors within lipid rafts, which is required for efficient downstream activation of naïve B cells. To test the hypothesis, we propose two aims that innovatively merge the fields of humoral immunity, toxicology, and membrane biochemistry/biophysics. Aim 1 will investigate how PFOA dysregulates the stability and abundance of B cell lipid rafts. Aim 2 will determine how PFOA dysregulates recruitment of specific receptors into lipid rafts and its functional consequences. Overall, this high risk/high reward study will establish B cell lipid raft biophysical organization as a new molecular target of PFOA. These studies will have a sustained impact by opening a new avenue of research focused on understanding how PFOA and other PFAS control lipid raft organization and function of differing B cell populations and other key cell types of humoral immunity. Ultimately, this line of research will improve our understanding of how PFAS exert immunotoxic effects, which can lead to targeted interventions and improved therapeutics in response to exposure.