Role of oxygen-sensing mechanism modulator, Mint3, in macrophage-related infl ammation and cancer

Abstract

The alpha subunit of HIF-1 can be suppressed by two types of oxygen-dependent hydroxylases: PHDs and FIH-1. Depletion of HIF-1α affects ATP production in macrophages under normoxic conditions, indicating that HIF-1α is necessary for macrophages to produce ATP via glycolysis even in the presence of oxygen. Consequently, there must be a mechanism that maintains HIF-1 activity in macrophages in the presence of normal oxygen levels. In this review we introduce Mint3, which activates HIF-1 transcriptional activity in limited cell types, including macrophages, under normoxic conditions. Mint3-deficient mice show no apparent abnormality, but macrophages from these mice have defective ATP production via glycolysis under normal oxygen conditions, similar to those from HIF-1α defi cient mice. Due to the defects in glycolysis and other HIF-1 target gene expression, macrophage hyperactivation is suppressed in Mint3-deficient mice and these mice are also resistant to acute inflammation, such as lipopolysaccharide (LPS)induced endotoxic shock and acute infl uenza pneumonia. Additionally, Mint3 depletion promotes pyroptosis in Listeria monocytogenes-infected macrophages, thereby attenuating Listeria proliferation and listeriosis. In the context of cancer, Mint3 depletion affects glycolysis and VEGFA production in inflammatory monocytes, resulting in reduced metastasis. Administration of naphthofluorescein which inhibits Mint3-mediated HIF-1 activation can also suppress cancer metastasis and LPS-induced septic shock in mice. Thus, Mint3 is an essential regulator of HIF-1 activity in macrophages under normoxic conditions and may be a good target for macrophage-involved cancer and infl ammatory disease treatment. Oxygen availability affects energy production and HIF-1 plays an essential role in adaptation to hypoxic conditions.