Journal
ALLERGY
Volume 69, Issue 6, Pages 752-762Publisher
WILEY-BLACKWELL
DOI: 10.1111/all.12407
Keywords
allergy; anaphylaxis; mast cell degranulation; mast cells; miRNA
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [SFB/TR22, A14]
- MRC [G0700287, G1001781] Funding Source: UKRI
- Medical Research Council [G1001781, G0700287] Funding Source: researchfish
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BackgroundMast cells (MCs) play a central role in allergic and inflammatory disorders by rapid degranulation and release of inflammatory mediators upon antigen-driven engagement of the Fc epsilon RI. Receptor-mediated MC responses are controlled by the activation of different isoforms of phosphoinositide-3-kinase (PI3K) and the downstream signaling processes. Recent evidence suggests that miRNAs are important molecular players regulating the PI3K/Akt pathway. MethodsThe role of miR-155 in the regulation of MC functions in vivo was studied in the passive cutaneous anaphylaxis (PCA) MC-dependent model. WT and miR-155(-/-) mice were injected intradermally with anti-DNP-IgE and intravenously with the antigen DNP-HSA. Ear swelling was assessed to evaluate the anaphylactic response. All investigations, to characterize miR-155 specific activities in MCs, were conducted comparing WT and miR-155(-/-) bone marrow-derived MCs (BMMCs). ResultsWe report that miR-155(-/-) mice display enhanced anaphylaxis reactions. Although miR-155(-/-)BMMCs show normal development, proliferation, and survival, miR-155 deficiency enhances Fc epsilon RI-mediated degranulation and release of TNF-, IL-13, and IL-6. Interestingly, the level of Akt phosphorylation on both of its regulatory residues Thr308 and Ser473 was increased in miR-155(-/-) compared to WT BMMCs. Gene expression profiling showed that miR-155(-/-)BMMCs exhibited significantly increased expression of the adapter PI3K subunits Pik3r5 (p101) and Pik3r6 (p84, p87(PIKAP)). Furthermore, selective blockade of the PI3K pathway inhibited degranulation in miR-155(-/-)BMMCs. ConclusionsThus, we suggest that miR-155 plays a critical role in Fc epsilon RI-mediated MC responses by modulating components of the PI3K pathway. This newly identified mechanism of miRNA-controlled MC activation may affect the initiation and maintenance of allergic disorders.
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