Brd4 regulates metabolic reprogramming of macrophages upon H. pylori infection.

Abstract

Abstract Metabolic reprogramming plays an important role in the regulation of several macrophage functions, including bacterial killing and cytokine production. Brd4 has emerged as a key innate immune response regulator by modulating the inflammatory cytokine expression in macrophages. However, the potential role of Brd4 in metabolic reprograming of macrophage activation remains unknown. Here, we showed that Brd4 facilitated a HIF-1α-dependent glycolytic shift for macrophage activation in response to H. pyloriinfection. H. pyloriinfection triggered Brd4-dependent polarization of macrophages to the M1 phenotype, which was associated with an increase in glycolysis and the upregulation of glycolytic genes, glucose transporter 1 (Glut1) and Hexokinase II (HK2). Mechanistically, Brd4 was recruited to the promoters of Glut1and Hk2by HIF-1α and regulated glycolysis by facilitating HIF-1α-dependent expression of Glut1and Hk2. Furthermore, we found that Brd4-mediated glycolysis was essential for M1 macrophage activation since the expression of iNOS, a marker of M1 polarization, was down-regulated in Brd4-deficient macrophages and could be rescued by the addition of pyruvate. Consistently, the iNOS-mediated killing of H. pyloriwas decreased in Brd4-deficient macrophages and also in mice with myeloid-specific deletion of Brd4. Our study identified a novel function of Brd4 in metabolic reprograming of macrophages through glycolysis and iNOS expression in response to bacterial infection. Supported by grant from NIH R03 AI163932