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

J Immunol. 2021 Nov 1;207(9):2359-2373. doi: 10.4049/jimmunol.2100108. Epub 2021 Sep 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / genetics
  • Arthritis, Rheumatoid / immunology*
  • Biomimetics / methods*
  • Cell Death
  • Cell Differentiation
  • Cells, Cultured
  • Cytokines / metabolism
  • Humans
  • Inflammatory Bowel Diseases / immunology*
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors
  • Interferon Regulatory Factor-1 / metabolism
  • Macrophages / immunology*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mechanistic Target of Rapamycin Complex 2 / metabolism*
  • Mitochondrial Proteins / genetics
  • NF-kappa B / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Th1 Cells / immunology
  • Tumor Necrosis Factor-alpha / metabolism


  • Apoptosis Regulatory Proteins
  • Cytokines
  • DIABLO protein, human
  • Inhibitor of Apoptosis Proteins
  • Interferon Regulatory Factor-1
  • Mitochondrial Proteins
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • RIPK1 protein, human
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases