Molecular mechanisms regulating macrophage response to hypoxia

Monocytes and Macrophages (Mo/Mφ) exhibit great plasticity, as they can shift between different modes of activation and, driven by their immediate microenvironment, perform divergent functions. These include, among others, patrolling their surroundings and main-taining homeostasis (resident Mo/Mφ), combating invading pathogens and tumor cells (classically activated or M1Mo/Mφ), orchestrating wound healing (alternatively activated or M2Mo/Mφ), and restoring homeostasis after an inflammatory response (resolution Mφ). Hypoxia is an important factor in the Mφ microenvironment, is prevalent in many physio-logical and pathological conditions, and is interdependent with the inflammatory response. Although Mo/Mφ have been studied in hypoxia, the mechanisms by which hypoxia influ-ences the different modes of their activation, and how it regulates the shift between them, remain unclear. Here we review the current knowledge about the molecular mechanisms that mediate this hypoxic regulation of Mφ activation. Much is known about the hypoxic transcriptional regulatory network, which includes the master regulators hypoxia-induced factor-1 and NF-κB, as well as other transcription factors (e.g., AP-1, Erg-1), but we also highlight the role of post-transcriptional and post-translational mechanisms. These mechanisms mediate hypoxic induction of Mφ pro-angiogenic mediators, suppress M1 Mφ by post-transcriptionally inhibiting pro-inflammatory mediators, and help shift the classically activated Mφ into an activation state which approximate the alternatively activated or resolution Mφ.