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The inflammasomes control the bioactivity of pro-inflammatory cytokines of the interleukin (IL)-1 family. The inflammasome assembled by NLRP3 has been predominantly studied in homogeneous cell populations in vitro, neglecting the influence of cellular interactions that occur in vivo. Here, we show that platelets boost the inflammasome capacity of human macrophages and neutrophils and are critical for IL-1 production by monocytes. Platelets license NLRP3 transcription, thereby enhancing ASC oligomerization, caspase-1 activity, and IL-1β secretion. Platelets influence IL-1β production in vivo, and blood platelet counts correlate with plasmatic IL-1β levels in malaria. Furthermore, we reveal an enriched platelet gene signature among the highest-expressed transcripts in IL-1β-driven autoinflammatory diseases. The platelet effect is independent of cell-to-cell contact, platelet-derived lipid mediators, purines, nucleic acids, and a host of platelet cytokines, and it involves the triggering of calcium-sensing receptors on macrophages. Hence, platelets provide an additional layer of regulation of inflammasomes and IL-1-driven inflammation., Competing Interests: Declaration of Interests E.L. is co-founder and consultant of IFM Therapeutics., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Inflammasomes are multiprotein complexes that detect and respond to foreign and endogenous danger signals by activating caspase-1; active caspase-1, in turn, matures the pro-inflammatory IL-1β family cytokines by cleaving their pro-forms into the biologically active cytokines. The upstream mechanisms leading to inflammasome activation, in particular for the NRLP3 inflammasome, remain poorly understood. Lu and colleagues identify a new function of Protein Kinase R (PKR) for activating the NLRP1, NLRP3, NLRC4 and AIM2 inflammasomes, thus identifying a potential new target for treating inflammasome-mediated diseases.