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 toward proinflammatory M1 state rendered them highly susceptible to the cytocidal effects of second mitochondria-derived activator of caspases mimetics (SMs), antagonist of the inhibitors of apoptosis proteins (IAPs), whereas M0 and anti-inflammatory M2c macrophages were resistant. In this study, 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, IFN regulatory factor-1, and mammalian target of rapamycin complex-1 (mTORC-1)/ribosomal protein S6 kinase pathways. 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 (cIAP)-2, receptor-interacting protein kinase (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-1, and RIPK-3 degradation through mTORC activation. Moreover, blocking cIAP-1/2, mTORC, or IFN regulatory factor-1 may represent a promising therapeutic strategy to control M1-associated diseases.

炎性巨噬细胞与许多疾病有关，包括类风湿性关节炎和炎性肠病。因此，靶向巨噬细胞功能和激活可能代表治疗巨噬细胞相关疾病的潜在策略。我们之前已经表明，IFN-γ 诱导的人类 M0 巨噬细胞向促炎 M1 状态的分化使它们对第二个线粒体衍生的半胱天冬酶模拟物 (SMs) 的细胞杀灭作用非常敏感，SMs 是凋亡蛋白抑制剂 (IAPs) 抑制剂的拮抗剂。 ，而 M0 和抗炎 M2c 巨噬细胞具有抗性。在这项研究中，我们研究了在分化为 M1 巨噬细胞和极化的 M1 巨噬细胞期间控制 SM 诱导的细胞死亡的机制。IFN-γ 刺激通过 Jak/STAT、IFN 调节因子-1 和哺乳动物雷帕霉素复合物靶标 1 (mTORC-1)/核糖体蛋白 S6 激酶通路赋予 M0 巨噬细胞对 SM 诱导的细胞死亡的敏感性。有趣的是，mTORC-1 独立于 M1 分化调节 SM 诱导的细胞死亡。相反，极化 M1 巨噬细胞中 SM 诱导的细胞死亡受 mTORC-2 通路调节。此外，SM 诱导的细胞死亡受细胞 IAP (cIAP)-2、受体相互作用蛋白激酶 (RIPK)-1 和 RIPK-3 在分化为 M1 巨噬细胞和极化 M1 巨噬细胞期间通过 mTORC 激活的降解的调节。与癌细胞系相反，M1 巨噬细胞中 SM 诱导的细胞死亡与内源性产生的 TNF-α 以及 NF-κB 通路无关。总的来说，SMs 对人 M1 巨噬细胞细胞死亡的选择性诱导可能是由 cIAP-2、RIPK-1 和 RIPK-3 降解通过 mTORC 激活介导的。此外，阻断 cIAP-1/2、mTORC 或 IFN 调节因子-1 可能代表控制 M1 相关疾病的有希望的治疗策略。