Abstract
Mast cells are critical actors of hypersensitivity type I (allergic) reactions by the release of vasoactive and proinflammatory mediators following their activation by aggregation of the high-affinity receptor for immunoglobulin E (FcεRI). We have previously identified Phospholipid Scramblase 1 (PLSCR1) as a new molecular intermediate of FcεRI signaling that amplifies degranulation of the rat mast cell line RBL-2H3. Here we characterized primary mast cells from Plscr1-/- mice. The absence of PLSCR1 expression did not impact mast cell differentiation as evidenced by unaltered FcεRI expression, general morphology, amount of histamine stored and expression of FcεRI signal effector molecules. No detectable mast cell deficiency was observed in Plscr1-/- adult mice. In dose-response and time-course experiments, primary cultures of mast cells (bone marrow-derived mast cells and peritoneal cell-derived mast cells) generated from Plscr1-/- mice exhibited a reduced release of β-hexosaminidase upon FcεRI engagement as compared to their wild-type counterparts. In vivo, Plscr1-/- mice were protected in a model of passive systemic anaphylaxis when compared to wild-type mice, which was consistent with an observed decrease in the amounts of histamine released in the serum of Plscr1-/- mice during the reaction. Therefore, PLSCR1 aggravates anaphylactic reactions by increasing FcεRI-dependent mast cell degranulation. PLSCR1 could be a new therapeutic target in allergy.
Highlights
Mast cells are involved in immune surveillance, inflammatory reactions and antibacterial/antiparasitic defenses [1, 2]
We reported that Phospholipid Scramblase 1 (PLSCR1) is highly phosphorylated on tyrosine residues following the engagement of FcεRI in the RBL-2H3 rat mast cell line [28] and in mouse bone marrowderived cultured mast cells (BMMC) [29]
The expression of FcεRI on the surface of BMMC and peritoneal cell-derived cultured mast cells (PCMCs) showed no detectable difference between the WT and Plscr1-/- cell populations (Fig 1B)
Summary
Mast cells are involved in immune surveillance, inflammatory reactions and antibacterial/antiparasitic defenses [1, 2]. FcεRI signaling is composed of multiple parallel, sequential and interconnected pathways such as the ones initiated by the Src-family tyrosine kinases Lyn and Fyn [3, 4]. These pathways involve the activation of the tyrosine kinase Syk, the phosphorylation of multiple signal intermediates such as the adaptors LAT1 and LAT2 and the mobilization of calcium. They result in the release of mast cell granule content into the extracellular milieu, in the production of arachidonic acid metabolites.
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