Macrophage responses to hypoxia: relevance to disease mechanisms

Abstract

Macrophages are ubiquitous in the stromal compartment of tissues under normal physiological conditions and the number of these cells increases markedly with the onset and progression of many pathological states. The mechanisms underlying this response are well described in such conditions as wound healing and malignant tumors, where tissue-specific signals enhance the extravasation of blood monocytes and their subsequent differentiation into macrophages. Recent evidence suggests that macrophages may also be stimulated by microenvironmental factors present in diseased tissues to perform distinct, tissue-specific activities. One such factor, hypoxia (low oxygen tension), results from insufficient vascular perfusion of a given tissue. Various studies have shown that experimental hypoxia alters the morphology, expression of cell surface markers, viability, phagocytosis, metabolic activity, and release of cytokines by macrophages. Here we review the evidence for these macrophage responses to hypoxia, the involvement of co-stimuli, and their implications for the role of macrophages in various disease processes. Because the intracellular mechanisms mediating the effects of hypoxia on gene expression in other cell types have been characterized recently, we discuss their possible involvement in the effects of hypoxia on gene expression in macrophages.

Hypoxia is a major stimulator of osteoclast formation and bone resorption

“…Responses to many osteolytic agents, including acidosis, are similarly prostaglandin-dependent in calvarial cultures . Prostaglandins also stimulate osteoclast formation (Collins and Chambers, 1992;Lader and Flanagan, 1998), and commonly mediate hypoxic responses in other cell types, such as macrophages (Lewis et al, 1999). Secondly, hypoxia stimulates purine nucleotide release from endothelial cells (Bodin and Burnstock, 1995), and we have previously shown that ATP and ADP are powerful osteolytic agents, acting through P2 receptors on bone cells (Morrison et al, 1998;Hoebertz et al, 2000Hoebertz et al, , 2001; this mechanism could account for some of the resorptive action of hypoxia in intact bone but it remains to be investigated whether nucleotide release from other cell types in bone might also be enhanced by low PO 2 .…”

“…Secondly, hypoxia stimulates purine nucleotide release from endothelial cells (Bodin and Burnstock, 1995), and we have previously shown that ATP and ADP are powerful osteolytic agents, acting through P2 receptors on bone cells (Morrison et al, 1998;Hoebertz et al, 2000Hoebertz et al, , 2001; this mechanism could account for some of the resorptive action of hypoxia in intact bone but it remains to be investigated whether nucleotide release from other cell types in bone might also be enhanced by low PO 2 . Thirdly, one of the major effects of hypoxia on cells is to stimulate the production of potent angiogenic factors such as VEGF, tumor necrosis factor-a, and fibroblast growth factors (Lewis et al, 1999); these factors are also stimulators of the formation and/or function of osteoclasts (Simmons and Raisz, 1991;Nakagawa et al, 1999Nakagawa et al, , 2000Suda et al, 2001). It is already well documented that hypoxia increases VEGF production by osteoblasts (Steinbrech et al, 1999(Steinbrech et al, , 2000aAkeno et al, 2001), and VEGF production by human peripheral blood-derived macrophages is also strongly upregulated by hypoxia (Lewis et al, 1999).…”

“…In environments such as the poorly vascularized yellow fatty bone marrow of the very elderly, or in inflamed tissue, infected tissue, tumors, wounds, and fracture sites, PO 2 could be considerably lower. In some diseased tissues, interstitial PO 2 may be less than 1% (Lewis et al, 1999). Thus, conventional tissue culture using atmospheric air exposes cells to oxygen tensions that are between $2.5 and !20 times higher than pathophysiological levels.…”

“…Hypoxia is well known to act as a stimulator of the formation and activation of cells derived from marrow precursors, including cells of the monocyte-macrophage lineage, which are closely related to osteoclasts (Bradley et al, 1978;Broxmeyer et al, 1990;Koller et al, 1992;Lewis et al, 1999). Only one early study (Stern et al, 1966) appears to have examined the effect of oxygen tension on a bone resorption parameter: the authors found that a moderate reduction in PO 2 (10%) was associated with decreased release of 3 H-proline from cultured calvaria, whereas hyperoxia (30-50%) had the opposite effect.…”

Picolinic acid- or desferrioxamine-inducible autocrine activation of macrophages engineered to produce IFNγ: an approach for gene therapy

“…A common denominator of many pathological lesions is hypoxia, a condition of low oxygen tension that occurs, for example, within the tumor mass or in inflammatory areas. Mf respond to hypoxia 9,10 and can be engineered to express therapeutic genes under these conditions 11,12 using synthetic promoters containing the hypoxia-responsive element (HRE), which is specifically transactivated under hypoxic conditions (reviewed in Lewis et al 10 and Semenza 13 ).…”