Macrophages play various roles in the body depending on the environment they reside due to their diversity and plasticity. Distinct functional phenotypes operate specific tasks, ranging from inflammation and host defense by M1 macrophages to promoting tumor progression and metastasis conducted by M2. Osteoclasts are a special type of macrophage involved in physiological bone remodeling and pathological bone degradation. The imbalance of each subtype of macrophages causes numerous dissimilar pathologies. The receptor interacting protein kinase 1 (RIPK1) is a regulator of inflammation and cell death in macrophages. It is poorly known how necroptosis is modulated or what determine the fate of a cell to enter apoptosis or necroptosis in the RIPK1-dependent pathway. Inhibitor of apoptosis protein (IAP) antagonists are under clinical trials for different forms of cancer and other diseases. As IAPs regulate RIPK1-dependent cell death in many cell types, and especially in immune cells like macrophages, knowledge about the effects of IAP antagonists on macrophage subtypes is necessary. This is to our knowledge not understood, and this is what we set out to investigate in this project. More understanding of precise mechanisms can lead to novel therapeutic approaches. This includes regulating or shifting the cell death program in order to bring advantageous outcomes with the least disastrous side-effects.
The IAP antagonist birinapant reduced the viability of human monocytes and increased cell death in macrophage subtypes in vitro. Apoptosis is thought to be the dominant form of RIPK1dependent cell death. However, the different modes of cell death in each subtype was assessed, including predominantly apoptosis, predominantly necroptosis, or the mixed phenotype of apoptosis and necroptosis. M1 macrophages were the most sensitive subtypes to cell death induction mediated by birinapant and they exhibited predominantly apoptotic phenotype while the rest were more susceptible to undergo necroptosis or displayed the mixed phenotype. Birinapant treatment also induced TNF-alpha secretion in M(IFN-gamma) macrophages while induced IL-1beta secretion in M(LPS) macrophages. In conclusion, we here showed that human monocytes and macrophage subtypes exhibit different responses to IAP antagonist birinapant regarding sensitivity and the pattern of cell death.