‘Hypoxia reprograms human macrophages towards a proinflammatory direction’

Abstract

Abstract Mononuclear phagocytes are recruited from the circulation as primary monocytes to sites of infection, inflammation, and tumor growth, where they undergo terminal differentiation into macrophages. Macrophages can be polarized into classically activated macrophages (M1) or alternatively activated macrophages (M2) which are characterized by a proinflammatory or an anti-inflammatory phenotype, respectively. M1 and M2 polarization is regulated by microenvironment factors. A common feature of pathologic situations is represented by hypoxia. Little is known about the impact of hypoxia on M1/M2 polarization. To address this issue, M1 (CD80+) and M2 (CD206+) macrophages were generated by culturing human monocytes with LPS or IL4 for 24h under normoxia (20%O2) or hypoxia (1%O2). We show that hypoxia amplifies the proinflammatory state of M1 macrophages and reprograms M2 macrophages towards a proinflammatory direction by increasing the production of inflammatory and proangiogenic cytokines/chemokines. The hypoxic pathologic microenvironment can tune the expression of immunoregulatory signaling receptors, whose deregulated expression may result in amplification of inflammation or establishment of immune escape situations. We demonstrate that hypoxia strongly upregulates the expression of one of such receptors, TREM -1, in M1 and M2 macrophages. Engagement of TREM-1 by agonist Ab triggers further production of M1-type cytokines/chemokines in both populations. These results suggest the role of the hypoxic environment present at pathologic sites in skewing macrophages towards a M1-like proinflammatory phenotype by inducing TREM-1, highlighting the potential of targeting TREM-1 in inflammatory disorders and in tumors.