Abstract 18584: The Hypoxic Microenvironment Alters Macrophage Lipid Metabolism and Reprograms Inflammatory Responses Through STAT3 and HIF1α Signaling
Background: Atherosclerosis is a chronic inflammatory disease mediated by numerous heterotypic interactions between cells and the microenvironment. Hypoxia in the arterial wall has been implicated in atherogenesis and is known to modulate immune responses. Macrophages, heterogeneous sentinels of the innate immune system, are involved in all phases of atherogenesis. In addition to their role in immune responses, macrophages are important orchestrators of systemic cholesterol metabolism. However, the molecular mechanisms underlying the relationship between macrophage inflammatory responses, lipid metabolism, and the hypoxic microenvironment remain poorly understood.
Objective: To examine the molecular effects of hypoxia on macrophage immune responses and cholesterol metabolism.
Methods and Results: Bone marrow-derived macrophages and RAW264.7 cells were stimulated with the Toll-like receptor ligand LPS (100 ng/ml for 2h) in the presence or absence of hypoxia (1% O2). Activation of inflammatory and metabolic signaling pathways and transcriptional profiles were examined. Macrophages stimulated with LPS demonstrated phosphorylation of MAPK (ERK, JNK, and p38) and STAT3 and stabilization of HIF1α. In contrast, LPS stimulation of hypoxic macrophages had increased HIF1α stabilization and blunting of STAT3 phosphorylation with essentially no changes in MAPK activation, suggesting that hypoxia differentially modulates LPS signaling pathways. Additionally, LPS stimulation led to distinct transcriptional changes in macrophage inflammatory (NOS2, TNFα, CD36, mannose receptor; p<0.005) and metabolic (PTGS2, ABCA1, ACAT1; p<0.005) profiles. These transcriptional profiles were greatly altered by hypoxia, mirroring the changes in activation of macrophage signaling pathways.
Conclusions: Hypoxia modulates macrophage inflammatory responses and their metabolic activity through differential activation of STAT3 and HIF1α and their transcriptional targets. These studies advance preliminary identification of close links between oxygen sensing and cholesterol biosynthesis, and highlight the potentially critical relationship between macrophages, metabolism, and the hypoxic microenvironment in atherogenesis.
- © 2012 by American Heart Association, Inc.