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Background: Cell death is a regulator of inflammation via the master cytokine IL-1.Results: Apoptotic stimuli induced a caspase-8-dependent release of IL-1β from macrophages. Necroptotic stimuli induced a calpain-dependent release of IL-1α.Conclusion: Mechanisms of cell death dictate the nature and form of IL-1 release.Significance: Sterile inflammatory responses may be determined by the mechanisms of cell death potentially allowing for selective interventions.

SummaryNLRP3 is a receptor important for host responses to infection, yet is also known to contribute to devastating diseases such as Alzheimer's disease, diabetes, atherosclerosis, and others, making inhibitors for NLRP3 sought after. One of the inhibitors currently in use is 2-aminoethoxy diphenylborinate (2APB). Unfortunately, in addition to inhibiting NLRP3, 2APB also displays non-selective effects on cellular Ca2+ homeostasis. Here, we use 2APB as a chemical scaffold to build a series of inhibitors, the NBC series, which inhibit the NLRP3 inflammasome in vitro and in vivo without affecting Ca2+ homeostasis. The core chemical insight of this work is that the oxazaborine ring is a critical feature of the NBC series, and the main biological insight the use of NBC inhibitors led to was that NLRP3 inflammasome activation was independent of Ca2+. The NBC compounds represent useful tools to dissect NLRP3 function, and may lead to oxazaborine ring-containing therapeutics.