CD36-mediated long-chain fatty acids transport in keratinocytes promotes psoriasis-like skin inflammation by increasing mitochondrial ROS.

Altered epidermal lipid metabolism along with keratinocyte dysfunction is a characteristic feature of psoriasis. CD36, a key fatty acid translocase, has been implicated in various inflammatory diseases through its regulation of lipid metabolism, but its role in the keratinocytes of psoriasis remains unclear. In this study, we found that CD36 was significantly elevated in the lesional epidermis of patients with psoriasis and positively correlated with the disease severity. Mice with keratinocyte-specific CD36 knockout or sulfosuccinimidyl oleate (the blocker of CD36) ointment topical treatment exhibited relieved imiquimod-induced psoriasis-like inflammation visually and histologically. Furthermore, gas chromatography tandem mass spectrometry analysis revealed significant increase of CD36 ligands, particularly long-chain fatty acids, in lesional skin from both patients with psoriasis and mice with imiquimod-induced psoriasis. In vitro, CD36 facilitated long-chain fatty acids transport into keratinocytes, leading to lipid accumulation and elevated expression of chemokines, notably CXCL2 and CCL20, which recruit neutrophils and CCR6+ T cells, respectively. Mechanistically, CD36-mediated long-chain fatty acids uptake impaired mitochondrial function and induced mitochondrial ROS generation, thereby activating the NF-κB signaling pathway and promoting chemokine production. These findings demonstrate an essential role of CD36 in lipid metabolic‒inflammatory crosstalk in keratinocytes, suggesting that it could be a potentially effective therapeutic target in inflammatory skin diseases.