Data Sheet 1_Human macrophages activate a coordinated program linking inflammation and cell death in response to intracellular Poly(I:C).pdf

TRIF-mediated signaling cascade and RIPK3 jointly contributed to caspase-8 activation leading to apoptosis. RIPK3 also promoted necroptosis by inducing MLKL phosphorylation. Downstream of caspases, Poly(I:C) induced cleavage of Gasdermin E (GSDME), which remained intracellular and localized in mitochondria contributing to the amplification of caspase-3 activation.

RIPK3-dependent signaling drove the release of IFN-β and TNF-α and promoted the upregulation of the sensors TLR3 and MDA5, thereby amplifying the inflammatory axis. The inflammatory response preceded cell death, with RIPK3 being the key regulator of the early signaling and TLR3/TRIF becoming involved at later timepoints. </p>Conclusions<p>Collectively, these findings identify RIPK3 as key mediator coordinating dsRNA-induced inflammatory signaling and regulated cell death in human macrophages.</p>