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 O-2-supplying blood vessel. However, it is not clear how the expression of MSR1 in macrophages is regulated by low pO(2). On the other hand, hypoxia-inducible factor (HIF)-1 alpha is well known to control hypoxic responses through regulation of hypoxia-inducible genes. Therefore, we investigated the effects of hypoxia and HIF-1 alpha on MSR1 expression and function in the macrophage cell line RAW264. Exposure to 1% O-2 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-1 alpha protein. The overexpression of HIF-1 alpha 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 MSR1 mRNA by hypoxia or CoCl2 was inhibited by YC-1, an inhibitor of HIF-1 alpha, or by the depletion of HIF-1 alpha expression by small interference RNA. These results indicate that hypoxia transcriptionally suppresses MSR1 expression through HIF-1 alpha.