Hypoxia-inducible factor-1α suppresses the expression of macrophage scavenger receptor 1

Macrophages are distributed in all peripheral tissues and play a critical role in the first line of the innate immune defenses against bacterial infection by phagocytosis of bacterial pathogens through the macrophage scavenger receptor 1 (MSR1). Within tissues, the partial pressure of oxygen (pO ₂) decreases depending on the distance of cells from the closest O₂-supplying blood vessel. However, it is not clear how the expression of MSR1 in macrophages is regulated by low pO₂. On the other hand, hypoxia-inducible factor (HIF)-1α is well known to control hypoxic responses through regulation of hypoxia-inducible genes. Therefore, we investigated the effects of hypoxia and HIF-1α on MSR1 expression and function in the macrophage cell line RAW264. Exposure to 1% O₂ or treatment with the hypoxia-mimetic agent cobalt chloride (CoCl₂) significantly suppressed the expression of MSR1 mRNA, accompanied by a markedly increase in levels of nuclear HIF-1α protein. The overexpression of HIF-1α in RAW264 cells suppressed the expression of MSR1 mRNA and protein, transcriptional activity of the MSR1 gene, and phagocytic capacity against the Gram-positive bacteria Listeria monocytogenes. The suppression of MSRl mRNA by hypoxia or C0Cl₂ was inhibited by YC-1, an inhibitor of HF-1α, or by the depletion of HIF-1α expression by small interference RNA. These results indicate that hypoxia transcriptionally suppresses MSR1 expression through HF-1α.