Mechanisms of allergy and clinical immunologyModulation of FcεRI-dependent mast cell response by OX40L via Fyn, PI3K, and RhoA
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Mice and reagents
C57BL/6 mice were purchased from Jackson Laboratories (Bar Harbor, Me) and were used in accordance with the animal study proposal A010-04-03 approved by the National Institutes of Health (NIH) and the National Institute of Arthritis, Musculoskeletal and Skin Diseases. C57BL/6 Tnfrsf4-deficient (OX40-deficient) mice were from Nigel Killeen (University of California, San Francisco). DNP-specific IgE was previously described.20 Di-nitro-phenyl (DNP)-human serum albumin (Ag) was purchased from
OX40L engagement impairs FcεRI activation and Gab2/PI3K/Akt, but not Syk/LAT, phosphorylation
The effect of OX40L engagement on FcεRI-mediated signaling early events was investigated in IgE/Ag-activated BM-derived MCs, in the absence or presence of sOX40. Phosphorylation of pY47 in FcεRI-γ subunit was ∼50% reduced 2 and 5 minutes after Ag triggering in the presence of sOX40 (Fig 1, A). This was followed by no significant alterations in Lyn-supported phosphorylation of Syk (Y323) or LAT (Y191) on OX40L engagement (Fig 1, B). In contrast, Fyn-mediated phosphorylation of Gab2 (Y452), PI3K
Discussion
Evidence of the OX40:OX40L axis as a crucial element for the maintenance of immunological tolerance is rapidly accumulating. Interference with this molecular interplay has been connected to the development of a proinflammatory microenvironment characterized by MC-dependent hyperresponsiveness, atopy, and autoimmunity in the host.31, 32
In the present work, we demonstrate that OX40L engagement blunts FcεRI-dependent MC activation in a manner that has not previously been appreciated.
MC
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Targeting the RhoA-GEF-H1 pathway of mast cells attenuates experimental airway allergy
2023, Archives of Biochemistry and BiophysicsBidirectional communication between mast cells and the gut-brain axis in neurodegenerative diseases: Avenues for therapeutic intervention
2021, Brain Research BulletinCitation Excerpt :Thus, the interaction between MCs and Treg cells could be OX40 L and OX40 dependent. It has been reported that OX40-OX40 L interactions suppresses the FcεRI-dependent degranulation of MCs that is associated with cAMP content within MCs (Sibilano et al., 2012). The degranulation of MCs requires an influx of Ca2+ influx through store-operated Ca2+ channels, where high cAMP concentrations in OX40L-stimulated MCs causes a decrease in Ca2+ influx and the subsequent inhibition of MC degranulation (Gri et al., 2008; Hua et al., 2007).
The Alternate Pathway for BCR Signaling Induced by IL-4 Requires Lyn Tyrosine Kinase
2021, Journal of Molecular BiologyCitation Excerpt :For example, after LMP2A transfection into BJAB cells, Lyn associates with LMP2A but Fyn does not, and this appears to depend on the SH2 domain of Lyn.41 In mast cells, Lyn and Fyn propagate signaling via two separate and distinct pathways involving different mediators.42 The generality of this explanation of a unique Lyn target is, however, questioned by the report that Fyn can phosphorylate PKCδtyr311 (although this was reported in a non-B cell type).43
IgE and mast cells: The endogenous adjuvant
2020, Advances in ImmunologyCitation Excerpt :It now appears that OX40L ligation on mast cells suppresses Fyn activation without interfering with Lyn-Syk-LAT, resulting in decreased PI3K and Akt activation with enhanced SHIP phosphorylation. Overall, this leads to a loss of PIP3 production and diminished calcium flux, a key regulator of granule fusion (Sibilano et al., 2012). Treg:MC synapse formation has been observed for both mouse and human cells (Frossi et al., 2011).
Potential effector and immunoregulatory functions of mast cells in mucosal immunity
2015, Mucosal ImmunologyIgE and Mast Cells. The Endogenous Adjuvant.
2015, Advances in Immunology
Supported by the Italian Ministry of Health, AIRC (Associazione Italiana Ricerca sul Cancro), Ministero dell'Istruzione, Università e Ricerca (PRIN 2009), Fondazione Compagnia di San Paolo, Turin, Italy, and the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (Bethesda, Md). S.P. was supported by a My First AIRC Grant (8726).
Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.
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Silvia Piconese is currently with the Dipartimento di Medicina Interna e Specialità Mediche, “Sapienza” Università di Roma, Policlinico Umberto I, Rome, Italy.