Different activation signals induce distinct mast cell degranulation strategies

Nicolas Gaudenzio, Riccardo Sibilano, Thomas Marichal, Philipp Starkl, Laurent L. Reber, Nicolas Cenac, Benjamin D. McNeil, Xinzhong Dong, Joseph D. Hernandez, Ronit Sagi-Eisenberg, Ilan Hammel, Axel Roers, Salvatore Valitutti, Mindy Tsai, Eric Espinosa*, Stephen J. Galli

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Mast cells (MCs) influence intercellular communication during inflammation by secreting cytoplasmic granules that contain diverse mediators. Here, we have demonstrated that MCs decode different activation stimuli into spatially and temporally distinct patterns of granule secretion. Certain signals, including substance P, the complement anaphylatoxins C3a and C5a, and endothelin 1, induced human MCs rapidly to secrete small and relatively spherical granule structures, a pattern consistent with the secretion of individual granules. Conversely, activating MCs with anti-IgE increased the time partition between signaling and secretion, which was associated with a period of sustained elevation of intracellular calcium and formation of larger and more heterogeneously shaped granule structures that underwent prolonged exteriorization. Pharmacological inhibition of IKK-β during IgE-dependent stimulation strongly reduced the time partition between signaling and secretion, inhibited SNAP23/STX4 complex formation, and switched the degranulation pattern into one that resembled degranulation induced by substance P. IgE-dependent and substance P-dependent activation in vivo also induced different patterns of mouse MC degranulation that were associated with distinct local and systemic pathophysiological responses. These findings show that cytoplasmic granule secretion from MCs that occurs in response to different activating stimuli can exhibit distinct dynamics and features that are associated with distinct patterns of MC-dependent inflammation.

Original languageEnglish
Pages (from-to)3981-3998
Number of pages18
JournalJournal of Clinical Investigation
Volume126
Issue number10
DOIs
StatePublished - 3 Oct 2016

Funding

FundersFunder number
ARRA1S10RR026780-01
Andrew Olson
Cell Science Imaging Facility
FP7-PEOPLE-2011-IOF299954
Lucile Packard Foundation for Children's Health
Plateau Technique Cytometrie
Plateau Technique Imagerie Cellulaire
Sophie Allart
Stanford NIH/National Center for Research Resources Clinical and Translational Science AwardUL1-RR025744
Stanford Neuroscience Microscopy Service
Toulouse CancerAI070813, AI023990, CA072074, U19-AI104209
National Institutes of HealthNS069375
National Institute of Allergy and Infectious DiseasesR01AI070813
National Center for Research ResourcesIFR30
H2020 Marie Skłodowska-Curie ActionsH2020-MSCA-IF-2014 656086
Philippe Foundation
Max Kade Foundation
European Commission
Agence Nationale de la Recherche
Institut national de la santé et de la recherche médicale
United States-Israel Binational Science Foundation2013263
Österreichischen Akademie der Wissenschaften
Austrian Science FundJ3399-B21
Fondation pour la Recherche MédicaleSPE20130326582
Seventh Framework Programme
Institut National du Cancer2012-054

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