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Hypoxia Prolongs Monocyte/Macrophage Survival and Enhanced Glycolysis Is Associated with Their Maturation under Aerobic Conditions¹

Department of Medicine, Arthritis and Inflammation Research Centre and Cooperative Research Centre for Chronic Inflammatory Diseases, University of Melbourne, The Royal Melbourne Hospital, Parkville, Victoria, Australia

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Health and Medical Research Council for a Senior Principal Research Fellowship to J.A.H.

² Address correspondence and reprint requests to Dr. John A. Hamilton, Department of Medicine, Arthritis and Inflammation Research Centre University of Melbourne, The Royal Melbourne Hospital, Clinical Sciences Building, Royal Parade, Parkville, Victoria 3050, Australia. E-mail address: jahami{at}unimelb.edu.au

³ Abbreviations used in this paper: DOG, deoxyglucose; BMM, bone marrow-derived macrophages; Glut, glucose transporter; HK, hexokinase; LDH, lactate dehydrogenase; MDM, monocyte-derived macrophage; PGK, phosphoglycerate kinase; qPCR, quantitative PCR.