title: 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.forename: Nicolas
authors.initials: N
authors.lastname: Gaudenzio
authors.forename: Riccardo
authors.initials: R
authors.lastname: Sibilano
authors.forename: Thomas
authors.initials: T
authors.lastname: Marichal
authors.forename: Philipp
authors.initials: P
authors.lastname: Starkl
authors.forename: Laurent L
authors.initials: LL
authors.lastname: Reber
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cenac
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: McNeil
authors.forename: Xinzhong
authors.initials: X
authors.lastname: Dong
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Hernandez
authors.forename: Ronit
authors.initials: R
authors.lastname: Sagi-Eisenberg
authors.forename: Ilan
authors.initials: I
authors.lastname: Hammel
authors.forename: Axel
authors.initials: A
authors.lastname: Roers
authors.forename: Salvatore
authors.initials: S
authors.lastname: Valitutti
authors.forename: Mindy
authors.initials: M
authors.lastname: Tsai
authors.forename: Eric
authors.initials: E
authors.lastname: Espinosa
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Galli
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D015550:Cell Degranulation; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000378:metabolism; D006801:Humans; D007073:Immunoglobulin E / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D013373:Substance P / Q000502:physiology
chemical_list: D018925:Chemokines; D047908:Intracellular Signaling Peptides and Proteins; D013373:Substance P; D007073:Immunoglobulin E