Activation of the JNK/COX-2/HIF-1α axis promotes M1 macrophage via glycolytic shift in HIV-1 infection.

Abstract

Chronic inflammation is recognized as a major risk factor for the severity of HIV infection. Whether metabolism reprogramming of macrophages caused by HIV-1 is related to chronic inflammatory activation, especially M1 polarization of macrophages, is inconclusive. Here, we show that HIV-1 infection induces M1 polarization and enhanced glycolysis in macrophages. Blockade of glycolysis inhibits M1 polarization of macrophages, indicating that HIV-1-induced M1 polarization is supported by enhanced glycolysis. Moreover, we find that this immunometabolic adaptation is dependent on hypoxia-inducible factor 1α (HIF-1α), a strong inducer of glycolysis. HIF-1α-target genes, including HK2, PDK1, and LDHA, are also involved in this process. Further research discovers that COX-2 regulates HIF-1α-dependent glycolysis. However, the elevated expression of COX-2, enhanced glycolysis, and M1 polarization of macrophages could be reversed by inactivation of JNK in the context of HIV-1 infection. Our study mechanistically elucidates that the JNK/COX-2/HIF-1α axis is activated to strengthen glycolysis, thereby promoting M1 polarization in macrophages in HIV-1 infection, providing a new idea for resolving chronic inflammation in clinical AIDS patients.