Platelet Adherent Eosinophils Drive ILC2 Expansion

Platelets are essential for leukocyte recruitment in allergic inflammation and can amplify type 2 immunopathology. Platelets contain the potent type 2 cytokine IL-33. Activated platelets adhere to circulating eosinophils in asthma and especially in aspirin-exacerbated respiratory disease (AERD). The intranasal administration of leukotriene C4 (LTC4) to ovalbumin (OVA) sensitized mice markedly increases lung eosinophilia in response to low dose (0.1%) OVA inhalation by a mechanism that requires platelets. We hypothesized that platelet-adherent eosinophils recruited to lung by LTC4 would increase group 2 innate lymphoid cell (ILC2) numbers and activation. OVA sensitized WT-C57BL/6 mice received intranasal LTC4 on three consecutive days after OVA challenge. AERD-like prostaglandin E2 synthase (Ptges-/-) mice were treated intranasally with 3 μg of house dust mite extract on 6 occasions, then were challenged with aerosolized Lys-aspirin (Lys-ASA) and airway resistance (RL) was measured. Anti-IL-5 antibody or isotype control was administered to determine their effects on ILC2 expansion and Lys-ASA. LTC4 challenge of OVA-sensitized WT mice markedly increased both total and platelet-adherent eosinophils in BAL and ILC2s in the lung, many of which expressed Ki67 and KLRG1. Neutralization of IL-5 prevented LTC4-induced increases in airway eosinophilia, ILC2 activation/proliferation, and BAL fluid CXCL7. The administration of anti-IL5 antibody to Ptges-/- mice also tended to suppress the ILC2 expansion while preventing platelet-dependent increases in CXCL7 and lung IL-33 during subsequent Lys-ASA challenges. Eosinophils, potentially through adherent platelets, may facilitate CysLT- and IL-33-driven ILC2 expansion and activation in AERD pathogenesis.