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

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 7

MC-mediated cutaneous inflammation exhibits different features depending on the nature of the MC activation stimulus.

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MC-mediated cutaneous inflammation exhibits different features depending...
Mice were sensitized by i.d. injection of 20 ng anti-DNP IgE into the left ear pinna, and vehicle alone was injected i.d. into the right ear pinna. Sixteen hours later, the right ear pinna was injected i.d. with 1 nmol of SP (pink) and the left with 5 ng of DNP-HSA (blue). In control experiments, both ear pinnae were injected i.d. with vehicle (black). (A) Evans blue extravasation in the ears of C57BL/6 WT mice. Left panel: representative photographs; right panel: quantification of Evans blue extravasation (OD 650 nm). (B) Same experiment as in A, but performed in MC-deficient C57BL/6 KitW-sh/W-sh mice versus C57BL/6 WT mice. (C) Same experiment as in A, but performed in Mrgprb2MUT mice versus littermate WT mice. (D) Changes (Δ) in ear thickness over time after i.d. injection of WT mice. (E) Representative H&E photomicrographs of sections of ear pinnae in mice sacrificed 360 minutes after i.d. injection. Scale bars: 200 μm; insets show boxed areas at higher magnification (×40). (F) Flow cytometry analysis of cells (CD45+ cells, neutrophils and monocytes) recovered from ear pinnae 360 minutes after i.d. injection of C57BL/6 mice. (A–D and F) Mean ± SEM; 2-tailed, unpaired t test (vehicle vs. SP or vehicle vs. DNP) or paired t test (SP vs. DNP-HSA). Two-way ANOVA (SP vs. DNP-HSA, DNP-HSA vs. vehicle and SP vs. vehicle); *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Data were pooled from 3 independent experiments, each of which gave similar results. n = total number of mice per condition.