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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 Article has an altmetric score of 6

Different activation signals induce distinct mast cell degranulation strategies

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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 6

Differences in the features of granule structures exteriorized after FcεRI- or MRGPRB2-mediated activation of mouse MCs in vivo.

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Differences in the features of granule structures exteriorized after Fcε...
(A) Mcpt5-Cre+ R26Y+ (Mcpt5-EYFP) mice were sensitized or not by i.d. injection into the ear pinna of 20 ng of mouse anti–2,4-dinitrophenyl (anti-DNP) IgE. Sixteen hours later, 8 μg of Av.SRho was injected i.d. into the same ear pinna. Nonsensitized mice were injected i.p. with 1 mg of SP. IgE-sensitized mice were injected i.p. with 500 μg of DNP-HSA. In control experiments, sensitized mice were injected i.p. with vehicle. 3D high-resolution single-cell images were taken, and Av.SRho fluorescence signal was modeled. (B) 3D photographs of the ear pinna 30 minutes after injection of vehicle (left panels) or DNP-HSA (right panels). Upper panels: Av.SRho (red) and EYFP (green) merged; lower panels: Av.SRho shown in pseudocolor intensity. Scale bars: 20 μm. (C) 3D analyses of ear pinna MC granule structures, 30 minutes after injection of vehicle (upper panels), DNP-HSA (middle panels), or SP (lower panels). Panels, left to right: Av.SRho (red) and EYFP (green) merged; isosurface modeling of Av.SRho (red) and EYFP (green); virtual isolation of released granule structures. Scale bars: 10 μm. (D) 3D modeled granule structures stained with pseudocolor as a function of their volume or their sphericity index. (E) Modeled volumes of granule structures (in cubic micrometers) following anti-IgE (blue) or SP (pink) injection. (F) Modeled sphericity indices of granule structures, following anti-IgE (blue) or SP (pink) injection. Left panel: each dot represents 1 individual granule structure analyzed; right panel: mean ± SEM of the data represented in the left panel. Two-tailed, unpaired t test; ***P < 0.001; ****P < 0.0001. Data represent approximately 1,000 single-granule structures analyzed from 3 experiments performed with 3 mice per condition, each of which gave similar results.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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