Abstract
Monocytes differentiate into macrophages, which deactivate invading pathogens. Macrophages can be resistant to cell death mechanisms in some situations, and the mechanisms involved are not clear. Here, using mouse immune cells, we investigated whether the differentiation of macrophages affects their susceptibility to cell death by the ripoptosome/necrosome pathways. We show that treatment of macrophages with a mimetic of second mitochondrial activator of caspases (SMAC) resulted in ripoptosome-driven cell death that specifically depended on tumor necrosis factor α (TNFα) expression and the receptor-interacting serine/threonine protein kinase 1 (RipK1)-RipK3-caspase-8 interaction in activated and cycling macrophages. Differentiation of macrophages increased the expression of pro-inflammatory cytokines but reduced RipK1-dependent cell death and the RipK3-caspase-8 interaction. The expression of the anti-apoptotic mediators, X-linked inhibitor of apoptosis protein (XIAP) and caspase-like apoptosis regulatory protein (cFLIPL), also increased in differentiated macrophages, which inhibited caspase activation. The resistance to cell death was abrogated in XIAP-deficient macrophages. However, even in the presence of increased XIAP expression, inhibition of the mitogen-activated protein kinase (MAPK) p38 and MAPK-activated protein kinase 2 (MK2) made differentiated macrophages susceptible to cell death. These results suggest that the p38/MK2 pathway overrides apoptosis inhibition by XIAP and that acquisition of resistance to cell death by increased expression of XIAP and cFLIPL may allow inflammatory macrophages to participate in pathogen control for a longer duration.
Highlights
Monocytes differentiate into macrophages, which deactivate invading pathogens
We show that treatment of macrophages with a mimetic of second mitochondrial activator of caspases (SMAC) resulted in ripoptosome-driven cell death that depended on tumor necrosis factor ␣ (TNF␣) expression and the receptorinteracting serine/threonine protein kinase 1 (RipK1)–RipK3– caspase-8 interaction in activated and cycling macrophages
We have evaluated the impact of macrophage differentiation on their susceptibility to cell death by the ripoptosome and necrosome pathway
Summary
Monocytes represent ϳ10% of the circulating leukocytes in human blood [20], which maintain homeostasis by replenishing the pool of tissue macrophages in steady state. Monocytes circulate in the blood for a few days before differentiating into macrophages or dendritic cells in the tissues in response to chemokines or cytokines [26]. Macrophages acquire resistance to cell death, but the mechanism has been unclear [27]. We have evaluated the impact of macrophage differentiation on their susceptibility to cell death by the ripoptosome and necrosome pathway. Our results indicate that macrophage differentiation results in increased expression of endogenous inhibitors of cell death, cFLIPL and XIAP, which promotes resistance to cell death by the ripoptosome pathway
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