Macrophage-mediated response to hypoxia in disease

Abstract

Hypoxia plays a critical role in the pathobiology of various inflamed, diseased tissues, including malignant tumors, atherosclerotic plaques, myocardial infarcts, the synovia of rheumatoid arthritic joints, healing wounds, and sites of bacterial infection. These areas of hypoxia form when the blood supply is occluded and/or the oxygen supply is unable to keep pace with cell growth and/or infiltration of inflammatory cells. Macrophages are ubiquitous in all tissues of the body and exhibit great plasticity, allowing them to perform divergent functions, including, among others, patrolling tissue, combating invading pathogens and tumor cells, orchestrating wound healing, and restoring homeostasis after an inflammatory response. The number of tissue macrophages increases markedly with the onset and progression of many pathological states, with many macrophages accumulating in avascular and necrotic areas, where they are exposed to hypoxia. Recent studies show that these highly versatile cells then respond rapidly to the hypoxia present by altering their expression of a wide array of genes. Here we review the evidence for hypoxia-driven macrophage inflammatory responses in various disease states, and how this influences disease progression and treatment.

Keywords: cytokine; hypoxia; inflammation; macrophage.

Figure 1

Schematic diagram of the HIF-1α pathway. Notes: In normoxia (A), PHDs hydroxylate specific proline residues of HIF-1α, leading to its proteosomal degradation, mediated by pVHL, an E3 ubiquitin ligase. During hypoxia (B), the lack of oxygen inhibits the actions of PHDs, and HIF-1α is not ubiquitinylated and then degraded. HIF-1α builds up and translocates to the nucleus where it binds to HIF-1β and p300. This complex then acts as a transcription factor that binds to HREs to induce expression of hypoxia-regulated genes. Abbreviations: UB, ubiquitin; HIF-1, hypoxia-inducible factor-1; OH, hydroxyl; VHL, von Hippel–Lindau protein; HRE, hypoxia response element; PHD, prolyl hydroxylase domain protein; p, phosphorylated.

Figure 2

Schematic representation of the role of macrophages following exposure to hypoxia in varying disease states. Notes: Macrophages are recruited as monocytes from circulation. They enter the hypoxic environment of the diseased tissue and upregulate cytokines/proteases (black arrows) that mediate downstream biological functions (gray boxes) in each disease state. The up arrows correspond to an increase in expression or activity; the down arrows correspond to a downregulation in expression or activity. Abbreviations: VEGF, vascular endothelial growth factor; MMP, matrix metalloproteinase; PGE2, prostaglandin E2; HGF, hepatocyte growth factor; IL10, interleukin 10; ORP150, oxygen-regulated protein 150; ROS, reactive oxygen species; TNF-α, tumor necrosis factor alpha; IL-1β, interleukin 1 beta; VLDLR, very low-density lipoprotein receptor; CCL2, chemokine (C-C motif) ligand 2; HIF-1, hypoxia-inducible factor-1; Mϕ, macrophage; ORP150, oxygen-regulated protein 150; RA, rheumatoid arthritis.