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

Published on May 1, 2019in Mucosal Immunology7.35
· DOI :10.1038/s41385-019-0134-8
Tao Liu9
Estimated H-index: 9
(Brigham and Women's Hospital),
Nora A. Barrett14
Estimated H-index: 14
(Harvard University)
+ 7 AuthorsJoshua A. Boyce48
Estimated H-index: 48
(Harvard University)
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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#1Lora G. Bankova (Brigham and Women's Hospital)H-Index: 12
#2Daniel F. Dwyer (Brigham and Women's Hospital)H-Index: 7
Last.Nora A. Barrett (Brigham and Women's Hospital)H-Index: 14
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#1Tao Liu (Brigham and Women's Hospital)H-Index: 9
#2Nora A. Barrett (Harvard University)H-Index: 14
Last.Joshua A. Boyce (Harvard University)H-Index: 48
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#1Erik Wambre (BRI: Benaroya Research Institute)H-Index: 17
#2Veronique Bajzik (BRI: Benaroya Research Institute)H-Index: 2
Last.Chester Ni (BRI: Benaroya Research Institute)H-Index: 6
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#1Alan T. Tang (UPenn: University of Pennsylvania)H-Index: 4
#2Jaesung Peter Choi (Centenary Institute)H-Index: 4
Last.Thomas Moore (U of C: University of Chicago)H-Index: 4
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#1Konstantin Stark (LMU: Ludwig Maximilian University of Munich)H-Index: 10
#2Vanessa Philippi (LMU: Ludwig Maximilian University of Munich)H-Index: 2
Last.Marie-Luise von Brühl (LMU: Ludwig Maximilian University of Munich)H-Index: 11
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