Targeting the ARF6-dependent recycling pathway to alter lipid rafts and reduce inflammation

Partitioning of inflammatory receptors into lipid rafts is essential for their function making lipid rafts a promising target for anti-inflammatory therapies. However, the practical application of lipid raft-targeted therapies has been limited by a lack of mechanistic understanding of their regulation. In this study, we demonstrate that targeting the Arf6-dependent recycling pathway effectively modifies lipid rafts and mitigates inflammation. Using Oxy210, a synthetic oxysterol, we observed significant anti-inflammatory effects both in vivo and in vitro. These effects were linked to an increased abundance of ABCA1, enhanced cholesterol efflux, and alterations in the abundance and composition of lipid rafts. Mechanistically, Oxy210 disrupted the recycling checkpoint in late endosomes by reducing the abundance and activation of the small GTPase Arf6 and decreasing PI(4,5)P2 levels. This impaired lipid raft recycling to the cell surface and simultaneously reduced ABCA1 internalization. These findings suggest an approach to modulate lipid rafts, with potential applications in treating inflammation, neurodegeneration, and infectious diseases.