Moderate Hypoxia Potentiates Interleukin-1β Production in Activated Human Macrophages
Rationale: Inflammation drives atherogenesis. Animal and human studies have implicated interleukin (IL)-1β in this disease. Moderate hypoxia, a condition that prevails in the atherosclerotic plaque, may conspire with inflammation and contribute to the evolution and complications of atherosclerosis through mechanisms that remain incompletely understood.
Objective: This study investigated the links between hypoxia and inflammation by testing the hypothesis that moderate hypoxia modulates IL-1β production in activated human macrophages.
Methods and Results: Our results demonstrated that hypoxia enhances pro-IL-1β protein--but not mRNA--expression in LPS-stimulated human macrophages. We show that hypoxia limits the selective targeting of pro-IL-1β to autophagic degradation, thus prolonging its half-life and promoting its intracellular accumulation. Furthermore, hypoxia increased the expression of NLRP3, a limiting factor in NLRP3 inflammasome function, and augmented caspase-1 activation in LPS-primed macrophages. Consequently, hypoxic human macrophages secreted higher amounts of mature IL-1β than did normoxic macrophages after treatment with crystalline cholesterol, an endogenous danger signal that contributes to atherogenesis. In human atherosclerotic plaques, IL-1β localizes predominantly to macrophage-rich regions that express activated caspase-1 and the hypoxia markers hypoxia-inducible factor 1α (HIF-1α) and hexokinase-2 (HK-2), as assessed by immunohistochemical staining of carotid endarterectomy specimens.
Conclusions: These results indicate that hypoxia potentiates IL-1β expression in cultured human macrophages and in the context of atheromata, therefore unveiling a novel pro-inflammatory mechanism that may participate in atherogenesis.
- Received May 22, 2014.
- Revision received August 31, 2014.
- Accepted September 2, 2014.