Protectin D1, an omega-3-derived lipid mediator, resolves mast cell-driven allergic inflammation via FcεRⅠ signaling

Abstract

Protectin D1 (PD1) derived from docosahexaenoic acid (DHA) has shown promise in resolving inflammation. Mast cells are critical drivers of allergic inflammation, releasing inflammatory mediators such as histamine and pro-inflammatory cytokines. This study assesses the effectiveness of PD1 in counteracting mast cell-mediated allergic inflammation. In vivo, two well-established mouse models were employed: IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin-induced active systemic anaphylaxis (ASA). The oral administration of PD1 markedly suppressed PCA reactions, including ear swelling, plasma extravasation of Evans blue and mast cell degranulation. In the ASA model, oral PD1 administration dose-dependently alleviated hypothermia and reduced elevated serum levels of IgE, histamine, and IL-4. Mechanistic insights were gained through studies in the RBL-2H3 and primary mast cells derived from mouse bone marrow, where PD1 inhibited IgE-mediated degranulation and decreased intracellular calcium influx by blocking FcεRⅠ signaling pathways involving Lyn, Fyn, and Syk kinases. Additionally, PD1 suppressed pro-inflammatory cytokine production by inhibiting the activity of critical transcription factor; nuclear factor-κB. These findings suggest that PD1, a bioactive lipid derived from DHA, is a very promising therapeutic candidate for mast cell-derived allergic inflammation.