STING agonists induce pyroptotic apoptosis in human monocytes

Abstract

Regulated cell death (RCD) represents a key outcome of the cyclic GMP GMP-AMP synthase (cGAS) cGAS)-stimulator of interferon genes (STING) activation in human monocytes, in addition to its canonical role in sensing cytoplasmic double double-stranded DNA and inducing secretion of type I and III interferons and proinflammatory cytokines. Pharmacological activation of cGAS cGAS-STING by STING agonists triggers a mixed RCD phenotype. Beyond induced cytokine release, it combines apoptotic mechanisms (caspase caspase-9, caspase caspase-8, and caspase caspase-3/7 activation) with pyroptotic features (caspase caspase-1 activation, gasdermin gasdermin-D cleavage, and secretion of mature interleukin interleukin-1 β and interleukininterleukin-18), while necroptosis is actively suppressed through caspase caspase-88-dependent cleavage of receptor receptor-interacting protein kinase 1 (RIPK1). This process is associated with mitochondrial dysfunction, which precedes caspase activation and likely functions both as a driving mechanism and a downstream consequence of cGAS cGAS-STING signaling via the STING STING-IRF3IRF3-BAX axis. Altogether, these findings define a distinc form of RCD in human monocytes referred to as pyroptotic apoptosis " and provide mechanistic insights into the noncanonical outcomes of cGAS cGAS-STING pathway.