A Two-Cell Model for IL-1β Release Mediated by Death-Receptor Signaling

Abstract

Summary: Interleukin-1β (IL-1β) is a key orchestrator of anti-microbial immunity whose secretion is typically dependent on activation of inflammasomes. However, many pathogens have evolved strategies to evade inflammasome activation. Here we describe an alternative, two-cell model for IL-1β release where invariant natural killer T (iNKT) cells use the death receptor pathway to instruct antigen-presenting cells to secrete IL-1β. Following cognate interactions with TLR-primed bone marrow-derived dendritic cells (BMDCs), iNKT cells rapidly translocate intracellular Fas ligand to the surface to engage Fas on BMDCs. Fas ligation activates a caspase-8-dependent signaling cascade in BMDCs that drives IL-1β release largely independent of inflammasomes. The apoptotic program initiated by Fas ligation rapidly transitions into a pyroptosis-like form of cell death mediated by gasdermin D. Together, our findings support a two-cell model for IL-1β secretion that may supersede inflammasome activation when cytosolic triggers fail. : How the immune system triggers IL-1β release during infection with inflammasome-evasive microbes is largely unknown. Donado et al. describe an alternative, caspase-8-dependent IL-1β secretion pathway where a second cell, the invariant natural killer T (iNKT) cell, can provide antigen-presenting cells with cell-extrinsic IL-1β release signals through FasL. Keywords: interleukin-1, inflammasome, cell death, Fas, Fas ligand, NKT cell, caspase, gasdermin, apoptosis, pyroptosis