Phosphatidylethanolamine alleviates OX-LDL-induced macrophage inflammation by upregulating autophagy and inhibiting NLRP1 inflammasome activation

Oxidized low-density lipoprotein (OX-LDL)-induced inflammation and Autophagy dysregulation are important events in the progression of atherosclerosis. Phosphatidylethanolamine (PE), a multifunctional phospholipid that is enriched in cells, has been proven to be directly involved in Autophagy which is closely associated with inflammation. However, whether PE can influence OX-LDL-induced Autophagy dysregulation and inflammation has not been reported. In the present study, we revealed that OX-LDL significantly induced macrophage inflammation through the CD36-NLRP1-caspase-1 signaling pathway in fish. Meanwhile, cellular PE levels were significantly decreased in response to OX-LDL induction. Based on the relationship between PE and Autophagy, we then examined the effect of PE supplementation on OX-LDL-mediated Autophagy impairment and inflammation induction in macrophages. As expected, exogenous PE restored impaired Autophagy and alleviated inflammation in OX-LDL-stimulated cells. Notably, Autophagy inhibitors reversed the inhibitory effect of PE on OX-LDL-induced maturation of IL-1β, indicating that the regulation of PE on OX-LDL-induced inflammation is dependent on Autophagy. Furthermore, the positive effect of PE on OX-LDL-induced inflammation was relatively conserved in mouse and fish macrophages. In conclusion, we elucidated the role of the CD36-NLRP1-caspase-1 signaling pathway in OX-LDL-induced inflammation in fish and revealed for the first time that altering PE abundance in OX-LDL-treated cells could alleviate inflammasome-mediated inflammation by inducing Autophagy. Given the relationship between OX-LDL-induced inflammation and atherosclerosis, this study prompts that the use of PE-rich foods promises to be a new strategy for atherosclerosis treatment in vertebrates.

Autophagy; IL-1β; Macrophages; NLRP1 inflammasomes; Oxidized low-density lipoprotein; Phosphatidylethanolamine.