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. Epub 2019 Jan 21.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma, Aspirin-Induced / immunology*
  • Blood Platelets / immunology*
  • Cells, Cultured
  • HMGB1 Protein / metabolism*
  • Humans
  • Interleukin-33 / metabolism
  • Leukotriene C4 / metabolism
  • Lung / immunology*
  • Lung / pathology
  • Male
  • Mast Cells / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Prostaglandin-E Synthases / genetics
  • Receptor for Advanced Glycation End Products / metabolism
  • Receptors, Leukotriene / genetics
  • Receptors, Leukotriene / metabolism*
  • Signal Transduction


  • HMGB1 Protein
  • Interleukin-33
  • Receptor for Advanced Glycation End Products
  • Receptors, Leukotriene
  • Leukotriene C4
  • cysteinyl leukotriene receptor 2
  • Prostaglandin-E Synthases
  • Ptges protein, mouse