Hypoxia Prolongs Monocyte/Macrophage Survival and Enhanced Glycolysis Is Associated with Their Maturation under Aerobic Conditions

Abstract

In chronic inflammatory lesions macrophages are abundant and adapt to the low oxygen concentrations often present there. In low oxygen some cell types die by apoptosis, as reported for macrophage cell lines, while others survive better as they shift their metabolism to anaerobic glycolysis. It was found here that hypoxia prolongs the survival of murine bone marrow-derived macrophages, either in the absence or presence of low CSF-1 (M-CSF) concentrations. Although Akt activity increased in bone marrow-derived macrophages in the low oxygen conditions, the levels of both anti- and proapoptotic Bcl-2 family members decreased. Glycolysis was enhanced as judged by increased glucose uptake, glucose transporter expression, lactate dehydrogenase mRNA expression, and lactate secretion. Human monocytes responded similarly to low oxygen, and a number of genes associated with glycolysis were shown by microarray analysis and quantitative PCR to be up-regulated. Interestingly, human monocyte-derived macrophages showed evidence of enhanced glycolysis even under aerobic conditions. It is proposed that certain monocyte/macrophage populations survive better under conditions of low oxygen, thereby contributing to their increased numbers at sites of chronic inflammation and tumors; it is also proposed that as macrophages differentiate from monocytes they begin to adopt a glycolytic metabolism allowing them to adapt readily when exposed to low oxygen conditions.

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

“…Hypoxia has been implicated in driving the proinflammatory response (17,29), although its role in relation to mitochondrial genome dysfunction in inflam- Figure 4. Mitochondrial DNA (mtDNA) mutations, reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP) in K4 cells exposed to normoxia (open bars) or 1% hypoxia (solid bars) and stimulated with superoxide dismutase (SOD), N-acetylcysteine (NAC), or dimethyloxalylglycine (DMOG).…”

Lack of the Transcription Factor Hypoxia-Inducible Factor 1α (HIF-1α) in Macrophages Accelerates the Necrosis of Mycobacterium avium-Induced Granulomas

“…Given that macrophages are the most abundant cells at the center of the granuloma, these might be the cells that die. However, macrophages are known to adapt to hypoxic conditions, namely by using the glycolytic pathway to generate ATP (14). Central to these metabolic adaptations is the transcription factor hypoxia-inducible factor 1␣ (HIF-1␣).…”

Oxidized Low-Density Lipoprotein Stimulates Macrophage 18F-FDG Uptake via Hypoxia-Inducible Factor-1α Activation Through Nox2-Dependent Reactive Oxygen Species Generation

“…PET using 18 F-FDG provides noninvasive imaging of atherosclerotic plaque inflammation (2). In human subjects, 18 F-FDG uptake in atherosclerotic lesions is increased in a manner that correlates to cardiovascular risk (3,4) and is reduced after drug treatment or risk modification (5,6). Thus, 18 F-FDG PET holds promise for monitoring disease progression and therapeutic response.…”

“…In human subjects, 18 F-FDG uptake in atherosclerotic lesions is increased in a manner that correlates to cardiovascular risk (3,4) and is reduced after drug treatment or risk modification (5,6). Thus, 18 F-FDG PET holds promise for monitoring disease progression and therapeutic response. However, to realize its full clinical potential, we crucially need a better understanding of how macrophage glucose metabolism is altered by the atherosclerotic microenvironment and the precise molecular mechanisms that regulate this metabolic response.…”