Selective killing of proinflammatory human M1 macrophages by SMAC mimetics and anti-inflammatory M2 macrophages by SMAC mimetics and caspase inhibitors

Abstract

Abstract The inflammatory and anti-inflammatory macrophages have been implicated in many diseases including rheumatoid arthritis, multiple sclerosis and leprosy. Targeting macrophage function and activation may represent a potential target to treat these diseases. Herein, we investigated the effect of second mitochondria-derived activator of caspases (SMAC) mimetics (SMs), the inhibitors of apoptosis (IAPs) proteins, on the killing of human pro- and anti-inflammatory macrophage subsets. We have shown previously, that human monocytes are susceptible to the cytotoxic effects of SMs, however, differentiated macrophages (M0) are resistant. Whether human macrophage subsets are also resistant to the cytotoxic effects of SM remains unknown. We show that differentiation of M0 macrophages towards M1 state rendered them highly susceptible to SM-induced cell death, whereas M2a, M2b and M2c subsets were resistant, with M2c being the most resistant. SM-induced cell death in M1 macrophages was mediated by apoptosis as well as necroptosis, and activated both extrinsic and intrinsic pathways of apoptosis. The susceptibility of M1 macrophages to SM-induced cell death was attributed to the IFNg-mediated polarization as JAK inhibitor reversed their susceptibility. In contrast, M2c and M0 macrophages experienced cell death through necroptosis pathway following simultaneous blockage of the IAPs pathways by SM and the caspase pathways by the pan-caspase inhibitors. Overall, the results suggest that survival of human macrophages is critically linked to the activation of the IAPs pathways. Moreover, agents blocking the cellular IAP1/2 and/or caspases can be exploited therapeutically to address inflammation-related diseases.