Caspase-8 silences cell death-independent constitutive immune activation driven by tonic TNF-α

Caspase-8 maintains organismal integrity by preventing cell death and secondary inflammation in selected epithelial and endothelial tissues. Here we show that caspase-8 also controls a systemic, cell death-independent inflammatory pathway that is constitutively activated during homeostasis. In vivo, selective caspase-8 inhibition produces, in the absence of other stimuli, marked neutrophilia driven by circulating proinflammatory and chemotactic cytokines. In vitro, caspase-8 inhibition triggers in neutrophils, but not in macrophages, a profound transcriptional response associated with the release of IL-1βand other cytokines. This process requires tonic TNF-α production by neutrophils, which acts autocrinally to sequentially activate RIPK1, RIPK3,MAPKs and NF-κB. The IL-1βrelease induced by caspase-8 inhibition requires gasdermin D and neutrophil serine proteases, but not canonical inflammasome components, such as NLRP3 and ASC, or gasdermin E. Our data unveil the mechanistic features of a neutrophil-centric, pro-inflammatory pathway that can be therapeutically targeted to augment host defenses against pathogenic agents.