W93 - Selective Induction of Cell Death in Human M1 Macrophages by Smac Mimetics is Mediated by cIAP-2 and RIPK-1/3 Through the Activation of mTORC

Inflammatory macrophages have been implicated in many diseases including rheumatoid arthritis and inflammatory bowel disease. Therefore, targeting macrophage function and activation may represent a potential strategy to treat macrophage-associated diseases. We have previously shown that IFN-γ-induced differentiation of human M0 macrophages towards pro-inflammatory M1 state rendered them highly susceptible to the cytocidal effects of second mitochondria-derived activator of caspases (SMAC) mimetics (SMs), the inhibitors of apoptosis (IAPs) proteins, whereas M0 and anti-inflammatory M2c macrophages were resistant. Herein, we investigated the mechanism governing SM-induced cell death during differentiation into M1 macrophages and in polarized M1 macrophages. IFN-γ stimulation conferred on M0 macrophages the sensitivity to SM-induced cell death through the Jak/STAT, interferon regulatory factor-1 (IRF-1) and the mammalian target of rapamycin complex-1/ribosomal protein S6 kinase (mTORC-1/S6K) pathway. Interestingly, mTORC-1 regulated SM-induced cell death independent of M1 differentiation. In contrast, SM-induced cell death in polarized M1 macrophages is regulated by the mTORC-2 pathway. Moreover, SM-induced cell death is regulated by cellular IAP-2 (cIAP-2), receptor-interacting protein kinase-1 (RIPK-1) and RIPK-3 degradation through mTORC activation during differentiation into M1 macrophages and in polarized M1 macrophages. In contrast to cancer cell lines, SM-induced cell death in M1 macrophages is independent of endogenously produced TNF-α as well as the NF-κB pathway. Collectively, selective induction of cell death in human M1 macrophages by SMs may be mediated by cIAP-2, RIPK-1and RIPK-3 degradation through mTORC activation. Moreover, blocking cIAP-1/2, mTORC or IRF-1 may represent a promising therapeutic strategy to control M1-assoiated diseases.