IAP proteins control polarization and immune-metabolism in committed macrophages

Inhibitors of Apoptosis Proteins (IAPs) regulate apoptosis in response to various cellular assaults. Using both genetic and pharmacological approaches we demonstrate here that the IAPs not only support opportunistic survival of intracellular human pathogens like Chlamydia pneumoniae but also controls plasticity of iNOS+ M1 macrophage during the course of infection and render them refractory for immune stimulation. Treatment of Th1 primed macrophages with birinapant (IAP specific antagonist) inhibited NO generation and relevant proteins involved in innate immune signalling. Accordingly, birinapant promoted hypoxia, angiogenesis and tumor induced M2 polarization of iNOS+ M1 macrophages. Interestingly, birinapant driven changes in immune signaling was accompanied with changes in the expression of various proteins involved in the metabolism thus revealing the new role of IAP proteins on immune metabolic reprogramming in committed macrophages. Microarray experiments were performed as dual-color hybridizations on Agilent 4x44K Whole Mouse Genome Microarrays. To compensate for dye-specific effects, a dye-reversal color-swap was applied.