646:
Cysteinyl Leukotriene Receptor 2 (CysLT2R) Drives Lung Immunopathology Through a High Mobility Box 1-Dependent Mechanism
Sunday, March 4, 2018: 4:30 PM
South Hall A2 (Convention Center)
Tao Liu, PhD, Nora A. Barrett, MD FAAAAI, Yoshihide Kanaoka, Tanya M. Laidlaw, MD FAAAAI, Eri Yoshimoto, Denise Garofalo, Chunli Feng, Joshua A. Boyce, MD FAAAAI

RATIONALE: Cysteinyl leukotrienes (cysLTs) act at both structural and hematopoietic cells to facilitate mucosal type 2 (eosinophilic) immunopathology. LTC4 acts at platelet-associated CysLT2R to upregulate lung endothelial adhesion receptors essential for antigen-induced eosinophil recruitment. Because platelets can release high mobility box 1 (HMGB1), a known inducer of type 2 immunopathology and endothelial activation, we sought to determine whether cysLTs elicit allergic lung inflammation through HMGB1 and the receptor for advanced glycation end products (RAGE).

METHODS: Ovalbumin-sensitized mice were challenged with aerosolized LTC4 for lung inflammation determination. Mouse platelets were stimulated with LTC4 analyzed for surface CD62P and HMGB1 by FACS analysis.

RESULTS: LTC4, but not its metabolites LTD4 or LTE4, induced surface expression of HMGB1 by mouse platelets in a CysLT2R-dependent manner. Blockade of RAGE prevented LTC4-induced platelet activation ex vivo. LTC4 challenge on ovalbumin-sensitized WT mice showed increased HMGB1, CXCL7, TXB2 in BAL. Neutralization of HMGB1 with a monoclonal Ab or blockade of RAGE with the selective antagonist prevented LTC4-induced increases in airway eosinophilia, platelet activation, and IL-5/IL-13 production. Depletion of platelets eliminated the LTC4-induced increase in HMGB1. Short-term HMGB1 neutralization prevented cysLT-driven reactions to inhaled lysine-aspirin in Ptges-/- mice, which exhibit a phenotype of aspirin exacerbated respiratory disease.

CONCLUSIONS: Platelet HMGB1 activates platelets in an autocrine loop that can drive type 2 lung immunopathology and aspirin sensitivity downstream of cysLT release. Antagonists of HMGB1 or RAGE may be useful to treat AERD and other disorders associated with type 2 immunpathology.