Hif-1α stabilisation polarises macrophages via cyclooxygenase/prostaglandin E2 in vivo [article]

Amy Lewis, Philip Michael Elks
2019 bioRxiv   pre-print
Macrophage subtypes are poorly characterised in disease systems in vivo. The initial innate immune response to injury and infectious stimuli through M1 polarisation is important for the outcome of disease. Appropriate macrophage polarisation requires complex coordination of local microenvironmental cues and cytokine signalling to influence immune cell phenotypes. If the molecular mechanisms behind macrophage polarisation were better understood then macrophages could be pharmacologically tuned
more » ... better deal with bacterial infections, for example tuberculosis. Here, using zebrafish tnfa:GFP transgenic lines as in vivo readouts of M1 macrophages, we show that hypoxia and stabilisation of Hif-1α polarises macrophages to a tnfa expressing phenotype. We demonstrate a novel mechanism of Hif-1α mediated macrophage tnfa upregulation via a cyclooxygenase/prostaglandin E2 axis, a mechanism that is conserved in human primary macrophages. These findings uncover a novel macrophage HIF/COX/TNF axis that links microenvironmental cues to macrophage phenotype that may have implications in inflammation, infection and cancer, where hypoxia is a common microenvironmental feature and where cyclooxygenase and Tnfa are major mechanistic players.
doi:10.1101/536862 fatcat:qjsx5lfddvcddbreajpejhxriy