2. Academic Validation
  3. Cysteinyl leukotriene receptor 2 drives lung immunopathology through a platelet and high mobility box 1-dependent mechanism

Cysteinyl leukotriene receptor 2 drives lung immunopathology through a platelet and high mobility box 1-dependent mechanism

  • Mucosal Immunol. 2019 May;12(3):679-690. doi: 10.1038/s41385-019-0134-8.
Tao Liu 1 2,  Nora A Barrett 1 2 3,  Yoshihide Kanaoka 1 2 3,  Kathleen Buchheit 1 2 3,  Tanya M Laidlaw 1 2 3,  Denise Garofalo 1 2,  Juying Lai 1 2,  Howard R Katz 1 2 3,  Chunli Feng 1 2,  Joshua A Boyce 4 5 6
Affiliations

Affiliations

  • 1 Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, USA.
  • 2 Jeff and Penny Vinik Center for Allergic Disease Research, Boston, MA, USA.
  • 3 Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 4 Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, USA. [email protected].
  • 5 Jeff and Penny Vinik Center for Allergic Disease Research, Boston, MA, USA. [email protected].
  • 6 Department of Medicine, Harvard Medical School, Boston, MA, USA. [email protected].
PMID: 30664709 DOI: 10.1038/s41385-019-0134-8
Abstract

Cysteinyl leukotrienes (cysLTs) facilitate eosinophilic mucosal type 2 immunopathology, especially in aspirin-exacerbated respiratory disease (AERD), by incompletely understood mechanisms. We now demonstrate that platelets, activated through the type 2 cysLT receptor (CysLT2R), cause IL-33-dependent immunopathology through a rapidly inducible mechanism requiring the actions of high mobility box 1 (HMGB1) and the receptor for advanced glycation end products (RAGE). Leukotriene C4 (LTC4) induces surface HMGB1 expression by mouse platelets in a CysLT2R-dependent manner. Blockade of RAGE and neutralization of HMGB1 prevent LTC4-induced platelet activation. Challenges of AERD-like Ptges-/- mice with inhaled lysine aspirin (Lys-ASA) elicit LTC4 synthesis and cause rapid intrapulmonary recruitment of platelets with adherent granulocytes, along with platelet- and CysLT2R-mediated increases in lung IL-33, IL-5, IL-13, and bronchoalveolar lavage fluid HMGB1. The intrapulmonary administration of exogenous LTC4 mimics these effects. Platelet depletion, HMGB1 neutralization, and pharmacologic blockade of RAGE eliminate all manifestations of Lys-ASA challenges, including increase in IL-33, mast cell activation, and changes in airway resistance. Thus, CysLT2R signaling on platelets prominently utilizes RAGE/HMGB1 as a link to downstream type 2 respiratory immunopathology and IL-33-dependent mast cell activation typical of AERD. Antagonists of HMGB1 or RAGE may be useful to treat AERD and Other disorders associated with type 2 immunopathology.

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