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

Caspase-8 is essential for maintaining organismal integrity by preventing cell death and subsequent inflammation in specific epithelial and endothelial tissues. Here, we show that caspase-8 also controls a systemic, cell death-independent inflammatory pathway that is constitutively active during homeostasis. In vivo, selective caspase-8 inhibition produces, in the absence of other stimuli, marked neutrophilia driven by circulating proinflammatory and chemotactic cytokines and promotes bacterial clearance during infection. In vitro, caspase-8 inhibition triggers in neutrophils, but not in macrophages, a profound transcriptional response associated with the release of IL-1β and 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-1β release induced by caspase-8 inhibition requires gasdermin D and neutrophil serine proteases, but not canonical inflammasome components. Our data uncover the mechanistic features of a neutrophil-centric, proinflammatory pathway that can be therapeutically targeted to augment host defenses against pathogens.