期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 126, 期 10, 页码 3981-3998出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI85538
关键词
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资金
- NIH [NS069375, AI023990, CA072074, AI070813, U19-AI104209]
- National Center for Research Resources [NCRR] [1S10RR026780-01]
- French Fondation pour la Recherche Medicate FRM [SPE20130326582]
- Philippe Foundation
- Lucile Packard Foundation for Children's Health
- Stanford NIH/National Center for Research Resources Clinical and Translational Science Award [UL1-RR025744]
- Marie Curie International Outgoing Fellowship for Career Development: European Union's Seventh Framework Programme (FP7-PEOPLE-IOF) [299954]
- Max Kade Fellowship of the Max Kade Foundation
- Austrian Academy of Sciences
- Austrian Science Fund (FWF) [J3399-B21]
- European Commission (Marie Sklodowska-Curie Individual Fellowship H2020-MSCA-IF) [656086]
- INSERM
- Institut National du Cancer [2012-054]
- Agence Nationale de la Recherche (Laboratoire d'Excellence Toulouse Cancer)
- United States-Israel Binational Science Foundation [2013263]
- Directorate for STEM Education
- Division Of Undergraduate Education [2013263] Funding Source: National Science Foundation
- Marie Curie Actions (MSCA) [656086] Funding Source: Marie Curie Actions (MSCA)
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-beta 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.
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