COX-1 mediates IL-33-induced extracellular signal-regulated kinase activation in mast cells: Implications for aspirin sensitivity.
J Allergy Clin Immunol
; 143(3): 1047-1057.e8, 2019 03.
Article
in En
| MEDLINE
| ID: mdl-30017554
ABSTRACT
BACKGROUND:
Classical FcεRI-induced mast cell (MC) activation causes synthesis of arachidonic acid (AA)-derived eicosanoids (leukotriene [LT] C4, prostaglandin [PG] D2, and thromboxane A2), which mediate vascular leak, bronchoconstriction, and effector cell chemotaxis. Little is known about the significance and regulation of eicosanoid generation in response to nonclassical MC activation mechanisms.OBJECTIVES:
We sought to determine the regulation and significance of MC-derived eicosanoids synthesized in response to IL-33, a cytokine critical to innate type 2 immunity.METHODS:
We used an ex vivo model of mouse bone marrow-derived mast cells and an IL-33-dependent in vivo model of aspirin-exacerbated respiratory disease (AERD).RESULTS:
IL-33 potently liberates AA and elicits LTC4, PGD2, and thromboxane A2 production by bone marrow-derived mast cells. Unexpectedly, the constitutive function of COX-1 is required for IL-33 to activate group IVa cytosolic phospholipase A2 with consequent AA release for synthesis of all eicosanoids, including CysLTs. In contrast, COX-1 was dispensable for FcεRI-driven CysLT production. Inhibition of COX-1 prevented IL-33-induced phosphorylation of extracellular signal-related kinase, an upstream effector of cytosolic phospholipase A2, which was restored by exogenous PGH2, implying that the effects of COX-1 required its catalytic function. Administration of a COX-1-selective antagonist to mice completely prevented the generation of both PGD2 and LTC4 in a model of AERD in which MC activation is IL-33 driven.CONCLUSIONS:
MC-intrinsic COX-1 amplifies IL-33-induced activation in the setting of innate type 2 immunity and might help explain the phenomenon of therapeutic desensitization to aspirin by nonselective COX inhibitors in patients with AERD.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Extracellular Signal-Regulated MAP Kinases
/
Cyclooxygenase 1
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Asthma, Aspirin-Induced
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Interleukin-33
/
Mast Cells
/
Membrane Proteins
Type of study:
Diagnostic_studies
Limits:
Animals
Language:
En
Journal:
J Allergy Clin Immunol
Year:
2019
Type:
Article