Type 2 Cysteinyl Leukotriene Receptors Drive IL-33–Dependent Type 2 Immunopathology and Aspirin Sensitivity

Abstract

Cysteinyl leukotrienes (cysLTs) facilitate mucosal type 2 immunopathology by incompletely understood mechanisms. Aspirin-exacerbated respiratory disease, a severe asthma subtype, is characterized by exaggerated eosinophilic respiratory inflammation and reactions to aspirin, each involving the marked overproduction of cysLTs. Here we demonstrate that the type 2 cysLT receptor (CysLTR), which is not targeted by available drugs, is required in two different models to amplify eosinophilic airway inflammation via induced expression of IL-33 by lung epithelial cells. Endogenously generated cysLTs induced eosinophilia and expanded group 2 innate lymphoid cells (ILC2s) in aspirin-exacerbated respiratory disease-like mice. These responses were mitigated by deletions of either or leukotriene C synthase (). Administrations of either LTC (the parent cysLT) or the selective CysLTR agonist N-methyl LTC to allergen sensitized wild-type mice markedly boosted ILC2 expansion and IL-5/IL-13 generation in a CysLTR-dependent manner. Expansion of ILC2s and IL-5/IL-13 generation reflected CysLTR-dependent production of IL-33 by alveolar type 2 cells, which engaged in a bilateral feed-forward loop with ILC2s. Deletion of blunted LTC-induced ILC2 expansion and eosinophilia but did not alter IL-33 induction. Pharmacological blockade of CysLTR prior to inhalation challenge of mice with aspirin blocked IL-33-dependent mast cell activation, mediator release, and changes in lung function. Thus, CysLTR signaling, IL-33-dependent ILC2 expansion, and IL-33-driven mast cell activation are necessary for induction of type 2 immunopathology and aspirin sensitivity. CysLTR-targeted drugs may interrupt these processes.

FTO intronic SNP strongly influences human neck adipocyte browning determined by tissue and PPARγ specific regulation: a transcriptome analysis

“…Ephrin type-A receptor 5 (EPHA5) which has a role in regulation of insulin secretion [64] was also highly expressed in DN as compared to SC brown adipocytes. Cysteinyl leukotriene receptor 2 (CYSLTR2) was shown to induce type 2 immune response in an interleukin (IL)-33 dependent manner [65]; this response was proposed but also debated to be a positive regulator of browning in mice [66,67]. In our experiments, transcripts of both genes were enriched in DN adipocytes.…”

Mechanical forces induce an asthma gene signature in healthy airway epithelial cells

“…S3), was detectable promptly after compression and was accompanied by a marked induction of epithelial alarmins, including IL-33 and TSLP. While a supportive activity of these factors has been documented for a variety of accessory immune cells 43,44 , IL-33 and TSLP are central for example to the initiation and enhancement of type 2 response typically seen in asthmatic inflammation [45][46][47][48] . Following compression (3 hr), an increased release of these factors from airway epithelial cells could activate type 2 innate lymphoid cells (ILC2) and augment type 2 inflammation in the lung 43,48,49 .…”

Role of lipid mediators and control of lymphocyte responses in type 2 immunopathology

“…Mouse lung ILC2s proliferate and generate IL-4, IL-13, and IL-5 in response to exogenous LTC 4 and LTD 4 , which can be blocked by CysLT 1 R antagonists and is absent in mice lacking CysLT 1 R. 38 LTC 4 and LTD 4 also synergize with IL-33 to promote T H 2 cytokine generation. 39,40 Notably, although LTC 4 , LTD 4 , and LTE 4 can all expand and activate lung ILC2s in mice, the effects of LTE 4 appeared to be indirect and (unlike human ILC2s) independent of CysLT 1 R. 39,41 These studies support a role for cysLTs in amplifying inflammation in type 2 immunity by acting at both the innate and adaptive lymphocyte compartments.…”

“…23 Additionally, lung EpC-derived IL-33 is sharply increased in Dermatophagoides farinae extract (Df)-treated microsomal PGE 2 synthase (Ptges) null mice, which show strong cysLT-driven type 2 pathology relative to WT control mice. The increase in IL-33 levels was abrogated in LTC 4 S-null mice, which was attributable to endogenous cysLT signaling through CysLT 2 R. 41,44 Given the ability of IL-33 to activate ILC2s synergistically with cysLTs acting at CysLT 1 R, 39 these findings imply cooperation between at least 2 cysLT receptors in regulating ILC2 homeostasis in inflammation.…”