Different activation signals induce distinct mast cell degranulation strategies
Nicolas Gaudenzio, … , Eric Espinosa, Stephen J. Galli
Nicolas Gaudenzio, … , Eric Espinosa, Stephen J. Galli
Published September 19, 2016
Citation Information: J Clin Invest. 2016;126(10):3981-3998. https://doi.org/10.1172/JCI85538.
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Research Article Immunology Inflammation

Different activation signals induce distinct mast cell degranulation strategies

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.

Authors

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

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Figure 1

Human MC activation by SP or anti-IgE induces different patterns of secretion of lipid mediators, cytokines, and chemokines.

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Human MC activation by SP or anti-IgE induces different patterns of secr...
IgE-sensitized or nonsensitized PBCMCs were incubated in the presence of anti-IgE (blue) or SP (pink), respectively, or with medium alone (no stimulation, black). (A) Percentage of β-hexosaminidase release 60 minutes after stimulation with different concentrations of stimulatory molecules. (B and C) Production of prostaglandin E2 (PGE2) (B) or PGD2 (C) 60 minutes after addition of 0.1, 1, or 10 μM SP or 0.02, 0.2, or 2 μg/ml of anti-IgE or medium alone. (D and E) Production of TNF-α, IL-13, GM-CSF, VEGF, and MCP-1 30 minutes (left panel), 90 minutes (middle panel), or 12 hours (right panel) after addition of 10 μM SP or 2 μg/ml of anti-IgE or medium alone (D) or 1 μM SP or 0.2 μg/ml of anti-IgE or medium alone (E). Mean ± SEM; 2-tailed, unpaired t test (vehicle vs. SP or vehicle vs. DNP); *P < 0.05; **P < 0.01; ***P < 0.001; nd, not detected. Data are pooled from 5 independent experiments performed with PBCMCs from 4 different donors, all of which gave similar results.