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<p>The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway senses double-stranded DNA in the cytoplasm, triggering the secretion of type I and III interferons and proinflammatory cytokines. However, cGAS–STING pathway activation by STING agonists also induces regulated cell death (RCD) in human monocytes, which is inherently linked to cytokine production. We identified that STING agonist-induced monocyte RCD integrates apoptotic (active caspase-9, -8 and -3/7) and pyroptotic mechanisms (active caspase-1, cleaved gasdermin-D and secreted mature interleukin-1β and -18), whereas necroptosis is inhibited through caspase-8-mediated cleavage of receptor-interacting protein kinase 1 (RIPK1). Additionally, this RCD is accompanied by mitochondrial dysfunction, which precedes caspase activation, suggesting that mitochondrial disruption may act as both the driving mechanism and a direct outcome of cGAS–STING pathway activation via the STING–IRF3–BAX pathway. Overall, this study identifies a novel RCD process that may be described as ‘pyroptotic apoptosis’, providing new insights into the outcomes of cGAS–STING signalling in human monocytes.</p><p></p>

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STING agonists trigger monocyte death via apoptosis, pyroptosis, caspase-8 activation and mitochondrial dysfunction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月31日

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  • Marketa Pimkova Polidarova,
  • Lydie Plecita-Hlavata,
  • Ivan Hirsch,
  • Klara Grantz Saskova,
  • Andrea Brazdova

摘要

The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway senses double-stranded DNA in the cytoplasm, triggering the secretion of type I and III interferons and proinflammatory cytokines. However, cGAS–STING pathway activation by STING agonists also induces regulated cell death (RCD) in human monocytes, which is inherently linked to cytokine production. We identified that STING agonist-induced monocyte RCD integrates apoptotic (active caspase-9, -8 and -3/7) and pyroptotic mechanisms (active caspase-1, cleaved gasdermin-D and secreted mature interleukin-1β and -18), whereas necroptosis is inhibited through caspase-8-mediated cleavage of receptor-interacting protein kinase 1 (RIPK1). Additionally, this RCD is accompanied by mitochondrial dysfunction, which precedes caspase activation, suggesting that mitochondrial disruption may act as both the driving mechanism and a direct outcome of cGAS–STING pathway activation via the STING–IRF3–BAX pathway. Overall, this study identifies a novel RCD process that may be described as ‘pyroptotic apoptosis’, providing new insights into the outcomes of cGAS–STING signalling in human monocytes.