Moderate Hypoxia Potentiates Interleukin-1β Production in Activated Human Macrophages

Abstract

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.

Inflammasome Priming in Sterile Inflammatory Disease

“…This study demonstrated that hypoxia could augment NLRP3 gene expression and protein levels in both LPS-treated and untreated human macrophages in vitro, and promoted pro-IL-1 production by limiting its autophagic degradation [20] .…”

“…Hypoxia is known to promote pro-IL-1 production and has been implicated in the pathogenesis of several diseases including atherogenesis, where patient samples display increased NLRP3-derived IL-1 production [20] . This study demonstrated that hypoxia could augment NLRP3 gene expression and protein levels in both LPS-treated and untreated human macrophages in vitro, and promoted pro-IL-1 production by limiting its autophagic degradation [20] .…”

Differential Regulation of Macrophage Glucose Metabolism by Macrophage Colony-stimulating Factor and Granulocyte-Macrophage Colony-stimulating Factor: Implications for 18F FDG PET Imaging of Vessel Wall Inflammation

“…Local production of M-CSF promotes the survival of foam cells and contributes to development of the early-stage, but not late-stage, atherosclerotic lesions (20,21 F-FDG PET studies (8)(9)(10)(11)(12)(13)(14). For example, glucose uptake and glycolysis are induced by bacterial-derived products, such as lipopolysaccharide (13), modified low-density lipoprotein (15,16), or hypoxia (17). However, the link between a proinflammatory macrophage phenotype and enhanced glucose uptake may be valid for only a number of stimuli and does not represent a universal phenomenon (9,14).…”

ATG16L1 Expression in Carotid Atherosclerotic Plaques Is Associated With Plaque Vulnerability

“…Of note, recent data have suggested that ischemic stress, such as moderate hypoxia, could potentiate inflammatory response in human primary macrophages. 34 Therefore, further analysis of different atherogenic stimuli in different cell types will be needed to better describe the pathways involved in the regulation of ATG16L1 expression.…”