TY - JOUR
T1 - Different activation signals induce distinct mast cell degranulation strategies
AU - Gaudenzio, Nicolas
AU - Sibilano, Riccardo
AU - Marichal, Thomas
AU - Starkl, Philipp
AU - Reber, Laurent L.
AU - Cenac, Nicolas
AU - McNeil, Benjamin D.
AU - Dong, Xinzhong
AU - Hernandez, Joseph D.
AU - Sagi-Eisenberg, Ronit
AU - Hammel, Ilan
AU - Roers, Axel
AU - Valitutti, Salvatore
AU - Tsai, Mindy
AU - Espinosa, Eric
AU - Galli, Stephen J.
N1 - Funding Information:
We thank all members of the Valitutti and Galli laboratories for discussions, and Chen Liu and Mariola Liebersbach for technical assistance. We also thank Andrew Olson and the Stanford Neuroscience Microscopy Service (supported by NIH NS069375), John Perrino and the Cell Science Imaging Facility (supported by ARRA Award 1S10RR026780-01 from the National Center for Research Resources [NCRR]; this article is solely the responsibility of the authors and does not necessarily represent the official views of the NCRR or the NIH), Fatima L'Faqihi (IFR30, Plateau Technique Cytometrie, Toulouse), and Sophie Allart (IFR30, Plateau Technique Imagerie Cellulaire, Toulouse) for technical assistance. N. Gaudenzio is supported by fellowships from the French "Fondation pour la Recherche Medicale FRM" (award SPE20130326582) and the Philippe Foundation. R. Sibilano is supported by a fellowship from the Lucile Packard Foundation for Children's Health and a Stanford NIH/National Center for Research Resources Clinical and Translational Science Award (UL1-RR025744). T. Marichal is supported by a Marie Curie International Outgoing Fellowship for Career Development: European Union's Seventh Framework Programme (FP7-PEOPLE-2011-IOF), grant 299954. P. Starkl was supported by a Max Kade Fellowship of the Max Kade Foundation and the Austrian Academy of Sciences and a Schroedinger Fellowship of the Austrian Science Fund (FWF), J3399-B21. Laurent L. Reber acknowledges support from the European Commission (Marie Skłodowska-Curie Individual Fellowship H2020-MSCA-IF-2014 656086) and INSERM. This work was supported by grants from the Institut National du Cancer (2012-054), the Agence Nationale de la Recherche (Laboratoire d'Excellence Toulouse Cancer) (to S. Valitutti), the NIH (grants AI023990, CA072074, AI070813, and U19-AI104209 to S.J. Galli), and the United States-Israel Binational Science Foundation (grant 2013263 to R. Sagi-Eisenberg, I. Hammel, and S.J. Galli).
PY - 2016/10/3
Y1 - 2016/10/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84991619659&partnerID=8YFLogxK
U2 - 10.1172/JCI85538
DO - 10.1172/JCI85538
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AN - SCOPUS:84991619659
SN - 0021-9738
VL - 126
SP - 3981
EP - 3998
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 10
ER -
