Abstract P054: Crosstalk Between Toll-like Receptor 4 and Lipid Metabolism Modulates Macrophage Survival

Abstract

Diabetes and obesity are well-established risk factors for cardiovascular disease, including atherosclerosis and adverse cardiac remodeling after myocardial infarction (MI). Abnormalities of lipid metabolism are a hallmark of diabetes and are strong predictors of the risk of future cardiac events. Macrophages are cells of the innate immune system that play a vital role in the host response to infection and tissue injury. In the cardiovascular system, macrophages are key participants in the pathogenesis of atherosclerosis and post-MI infarct remodeling. Toll-like receptor (TLR)-4 is highly active on macrophages and has been shown to contribute to the injury response in the heart and vasculature. Thus, understanding how lipids modulate TLR4-mediated macrophage responses is particularly relevant to diabetic cardiovascular disease. To investigate this question, we studied the effect of palmitate; an abundant dietary saturated fatty acid, on macrophage viability and inflammatory signaling after stimulation with the TLR4 ligand LPS. Interestingly, LPS or palmitate alone failed to trigger significant cell death; however, the combination of these stimuli markedly reduced macrophage viability. The synergistic death induced by LPS and palmitate required functional TLR4, yet occurred independently of ER stress, reactive oxygen species generation, ceramide production, caspase activation and autophagy. Instead, lysosomal integrity is compromised early and followed by the loss of mitochondrial membrane potential and ultimately cell death. Interestingly, inhibition of the lipid remodeling enzyme iPLA2 attenuates lysosomal instability and cell death following treatment with palmitate/LPS. Thus, we describe a novel cell death response in macrophages that occurs via a mechanism involving iPLA2 activation and lysosomal destabilization. These data provide evidence that the lipid environment modulates macrophage function following inflammatory stimuli. Given the critical role of macrophages in the response to tissue injury, these findings are highly relevant to understanding cardiac injury and repair in diabetics.