Platelets fuel the inflammasome activation of innate immune cells

Rolfes, V.; Ribeiro, L. S.; Hawwari, I.; Buotcher, L.; Rosero, N. S.; Maasewerd, S.; Santos, M. L. S.; Schmidt, S. V.; Rothe, M.; Stunden, J.; Carvalho, L. H.; Fontes, C. J.; Prochnicki, T.; Arditi, M.; Latz, E.; Franklin, B. S.

doi:10.1101/800771

bioRxiv · 10.1101/800771

Platelets fuel the inflammasome activation of innate immune cells

Rolfes, V.·Ribeiro, L. S.·Hawwari, I.·Buotcher, L.·Rosero, N. S.·Maasewerd, S.·Santos, M. L. S.·Schmidt, S. V.·Rothe, M.·Stunden, J.·Carvalho, L. H.·Fontes, C. J.·Prochnicki, T.·Arditi, M.·Latz, E.·Franklin, B. S.

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Abstract

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 homogenous cell populations in vitro, neglecting the influence of cellular interactions that occur in vivo. Here, we show that platelets, the second most abundant cells in the blood, 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 nucleation, caspase-1 activity, and IL-1{beta} maturation. Platelet depletion attenuated LPS-induced IL-1{beta} in vivo, and platelet counts correlate with plasma concentrations of IL-1{beta} in malaria patients. Furthermore, a platelet gene signature was enriched among the highest expressed transcripts in IL-1{beta}-driven autoinflammatory diseases. The platelet-mediated enhancement of inflammasome activation was independent of cell-to-cell contacts, platelet-derived lipid mediators, purines, nucleic acids and a host of platelet cytokines, and involved the triggering of calcium sensing receptors on macrophages by a calcium-dependent protein commonly released by platelets and megakaryocytes. Finally, we report that platelets provide an additional layer of regulation of inflammasomes in vivo.

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Rolfes, V., Ribeiro, L. S., Hawwari, I., Buotcher, L., Rosero, N. S., Maasewerd, S., Santos, M. L. S., Schmidt, S. V., Rothe, M., Stunden, J., Carvalho, L. H., Fontes, C. J., Prochnicki, T., Arditi, M., Latz, E., Franklin, B. S.. 2019-10-11. Platelets fuel the inflammasome activation of innate immune cells. https://doi.org/10.1101/800771

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