Alternative inflammasome activation enables IL-1β release from living cells

Abstract

Classical modes of NLRP3 activation entail a priming step that enables its activation (signal 1) and a potassium efflux-dependent activation signal (signal 2) that triggers pyroptosome formation and pyroptosis, a lytic cell death necessary for IL-1β release. Opposing to that, human monocytes engage an alternative NLRP3 inflammasome pathway in response to LPS that proceeds in the absence of signal 2 activation and enables IL-1β secretion without pyroptosis. This specifically relies on Caspase-8 to propagate signaling to NLRP3, leading to inflammasome activation in absence of pyroptosome formation. Here, we summarize the current knowledge about alternative inflammasome activation, discuss potential extensions of this signaling entity beyond LPS-dependent activation, speculate about its role in tissue homeostasis and sterile inflammation and highlight the implications of pyroptosis-independent IL-1β secretion.

Figure 1. The alternative inflammasome comprises a signaling entity distinct from classical inflammasome activation.

Classical activation of the NLRP3 inflammasome involves a two-step activation model (left side of figure): a PRR-derived signal (signal 1) is required to license NLRP3 activation via upregulation of its expression at the transcriptional level and/or its posttranslational modification. NLRP3 can now detect perturbations of cellular integrity by recognizing potassium efflux (signal 2). Consequently, Nek7–NLRP3 interaction leads to pyroptosome assembly and Caspase-1 activation to mature IL-1β and GSDMD. Pore formation of GSDMD induces pyroptosis, which is critically required for IL-1β secretion. Opposing to that alternative inflammasome activation can be triggered by one signal only, for example, LPS or an iNKT cell derived signal (right side of figure): LPS sensing induces a TLR4-TRIF-RIPK1-FADD-CASP8 signaling axis, resulting in activation of NLRP3 by cleavage of an unknown Caspase-8 substrate independently of potassium efflux. The alternative NLRP3 activation complex is different from the pyroptosome and possibly displays stoichiometric composition. Although Caspase-1 becomes matured and cleaves IL-1β, pyroptosis is not induced and IL-1β is secreted by an unconventional mechanism that functions independently of GSDMD.