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Analyzing the Functions of Mast Cells In Vivo Using 'Mast Cell Knock-in' Mice
Published on: May 27, 2015
miRNA-155 controls mast cell activation by regulating the PI3Kγ pathway and anaphylaxis in a mouse model
K Biethahn1, Z Orinska, E Vigorito
1Research Center Borstel, Borstel, Germany.
Background:
Mast 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 FcεRI. 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.
Methods:
The 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).
Results:
We report that miR-155(-/-) mice display enhanced anaphylaxis reactions. Although miR-155(-/-) BMMCs show normal development, proliferation, and survival, miR-155 deficiency enhances FcεRI-mediated degranulation and release of TNF-α, 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 PI3Kγ subunits Pik3r5 (p101) and Pik3r6 (p84, p87(PIKAP) ). Furthermore, selective blockade of the PI3Kγ pathway inhibited degranulation in miR-155(-/-) BMMCs.
Conclusions:
Thus, we suggest that miR-155 plays a critical role in FcεRI-mediated MC responses by modulating components of the PI3Kγ pathway. This newly identified mechanism of miRNA-controlled MC activation may affect the initiation and maintenance of allergic disorders.
Insights
MicroRNA-155 (miR-155) deficiency enhances mast cell degranulation and allergic reactions by modulating the PI3Kγ pathway. This suggests miR-155 is a critical regulator of mast cell activation in allergic disorders.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- Mast cells (MCs) are key players in allergic and inflammatory responses, mediating reactions through degranulation upon FcεRI activation.
- Phosphoinositide-3-kinase (PI3K) signaling pathways are crucial for MC activation.
- MicroRNAs (miRNAs) are emerging as regulators of PI3K/Akt signaling.
Purpose of the Study:
- To investigate the role of microRNA-155 (miR-155) in regulating mast cell (MC) function and allergic responses.
- To elucidate the molecular mechanisms by which miR-155 influences MC activation via the PI3K pathway.
Main Methods:
- Utilized a passive cutaneous anaphylaxis (PCA) mouse model to study MC-dependent allergic reactions in wild-type (WT) and miR-155 knockout (miR-155(-/-)) mice.
- Compared WT and miR-155(-/-) bone marrow-derived mast cells (BMMCs) to analyze FcεRI-mediated degranulation and mediator release.
- Assessed Akt phosphorylation and gene expression of PI3K isoforms in BMMCs.
Main Results:
- miR-155(-/-) mice exhibited enhanced anaphylaxis reactions compared to WT mice.
- miR-155 deficiency in BMMCs led to increased FcεRI-mediated degranulation and release of inflammatory cytokines (TNF-α, IL-13, IL-6).
- Increased Akt phosphorylation and elevated expression of PI3Kγ subunits (Pik3r5, Pik3r6) were observed in miR-155(-/-) BMMCs, with PI3Kγ pathway blockade inhibiting degranulation.
Conclusions:
- miR-155 negatively regulates FcεRI-mediated mast cell responses by modulating components of the PI3Kγ pathway.
- This study identifies a novel miRNA-dependent mechanism controlling mast cell activation, potentially impacting allergic disease development and progression.
