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Hypoxia reduces CD80 expression on monocytes but enhances their LPS-stimulated TNF-alpha secretion
Nitza Lahat1, Michal A Rahat, Mouna Ballan
1Immunology Research Unit, Carmel Medical Center, Rappaport Family Institute for Research in the Medical Sciences, and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel. rahat_miki@clalit.org.il
Abstract:
Monocytes/macrophages in ischemic tissues are involved in inflammation and suppression of adaptive immunity via secretion of proinflammatory cytokines and reduced ability to trigger T cells, respectively. We subjected human mononuclear cells and mouse macrophages to hypoxia and reoxygenation, the main constituents of ischemia and reperfusion, and added lipopolysaccharide (LPS) to simulate bacterial translocation, which frequently accompanies ischemia. We monitored the secretion of tumor necrosis factor alpha (TNF-alpha) and the surface expression of human leukocyte antigen-DR and the costimulatory molecules CD80 and CD86 on monocytes/macrophages. Hypoxia selectively reduced the surface expression of CD80 (P<0.01), and synergistically with LPS, it enhanced TNF-alpha secretion (P<0.003). Reoxygenation reversed both phenomena. In the mouse macrophage cell line RAW 264.7, hypoxia reduced the surface expression of CD80 and increased its concentrations in the supernatants (P<0.01). Down-regulation of the mRNA coding for the membrane-anchored CD80 was observed, suggesting that hypoxia triggers alternative splicing to generate soluble CD80. Cumulatively, these results suggest that hypoxia simultaneously affects monocytes/macrophages to enhance inflammation and reduce their ability to initiate adaptive-immunity responses associated with ischemic injury.
Insights
Hypoxia during ischemia impairs monocyte/macrophage function, reducing CD80 expression and enhancing inflammatory cytokine release. Reoxygenation reverses these effects, impacting adaptive immunity during ischemic injury.
Area of Science:
- Immunology
- Cell Biology
- Pathophysiology
Background:
- Monocytes/macrophages in ischemic tissues contribute to inflammation and suppress adaptive immunity.
- Ischemia/reperfusion involves hypoxia and reoxygenation, often accompanied by bacterial translocation.
Purpose of the Study:
- To investigate the effects of hypoxia and lipopolysaccharide (LPS) on human mononuclear cells and mouse macrophages.
- To analyze the secretion of tumor necrosis factor alpha (TNF-alpha) and surface expression of CD80/CD86.
Main Methods:
- Human mononuclear cells and mouse macrophages were subjected to hypoxia and reoxygenation.
- Lipopolysaccharide (LPS) was added to simulate bacterial translocation.
- Secretion of TNF-alpha and surface expression of CD80/CD86 were monitored.
Main Results:
- Hypoxia selectively reduced CD80 surface expression and, with LPS, enhanced TNF-alpha secretion.
- Reoxygenation reversed these hypoxia-induced changes.
- Hypoxia led to reduced membrane-bound CD80 and increased soluble CD80 in mouse macrophages.
Conclusions:
- Hypoxia impairs monocyte/macrophage function during ischemic injury.
- This impairment involves enhanced inflammation and reduced capacity to initiate adaptive immunity.
- Alternative splicing may generate soluble CD80 under hypoxic conditions.