IL-10 attenuates OxPCs-mediated lipid metabolic responses in ischemia reperfusion injury
Ashim K. Bagchi, Arun Surendran, Akshi Malik, Davinder S. Jassal, Amir Ravandi, Pawan K. Singal
Abstract
Abstract Oxidized phospholipids (OxPLs) promote inflammation as well as low density lipoprotein (LDL) uptake in a variety of physiological and pathological states. Given the anti-inflammatory role of the cytokine IL-10, we investigated its modulatory effect on the production of oxidized phosphatidylcholines (OxPCs) as well as lipid metabolic responses in global myocardial ischemia/reperfusion (I/R) injury. Increased OxPCs levels, by 1-Palmitoyl-2-(5-oxovaleryl)-sn-glycero-3-phosphocholine (POVPC), promoted oxidative stress (OS) and cell death. OxPCs-mediated-OS, resulted in oxidized low-density lipoprotein receptor 1 (LOX-1) activation and upregulated the expression of toll-like receptor 2 (TLR2). IL-10-induced increase in proprotein convertase subtilisin/kexin type 9 (PCSK9) negatively regulated LOX-1 as well as TLR2 inflammatory responses. Under stress conditions, phosphorylation of sterol regulatory element binding protein 1c (SREBP 1c) was prevented by IL-10. The latter also prevented the generation of OxPCs and reduced their ratio (OxPCs/PCs) during injury. LOX-1 activation also promoted SREBP1c-mediated TGF-βRII expression which was inhibited by IL-10. Both fragmented and non-fragmented OxPCs were elevated during I/R and this effect was attenuated by IL-10. The largest impact (two–threefold change at log 2 ) was on PAzPC, (1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine)—a fragmented OxPC. Thus it appears that among different OxPCs, IL-10 significantly reduces a single molecule (PAzPC)-mediated lipid metabolic responses in cardiomyocytes thereby mitigating inflammation and cell death.