title: miRNA-155 controls mast cell activation by regulating the PI3Kγ pathway and anaphylaxis in a mouse model.
abstract: 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.
authors.affiliation: Research Center Borstel, Borstel, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Biethahn
authors.forename: Z
authors.initials: Z
authors.lastname: Orinska
authors.forename: E
authors.initials: E
authors.lastname: Vigorito
authors.forename: D A
authors.initials: DA
authors.lastname: Goyeneche-Patino
authors.forename: F
authors.initials: F
authors.lastname: Mirghomizadeh
authors.forename: N
authors.initials: N
authors.lastname: Föger
authors.forename: S
authors.initials: S
authors.lastname: Bulfone-Paus
mesh_terms: D000707:Anaphylaxis / Q000209:etiology*; D000818:Animals; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: allergy; anaphylaxis; mast cell degranulation; mast cells; miRNA