Altered subcellular localization of IL-33 leads to non-resolving lethal inflammation

Bessa, Juliana; Meyer, Claas A.; Mudry, Maria Cristina De Vera; Schlicht, Sonja; Smith, Susan; Iglesias, Antonio; Cote-Sierra, Javier

doi:10.1016/j.jaut.2014.02.012

Cited by 144 publications

(149 citation statements)

References 50 publications

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“…The nuclear domain plays a critical role in the regulation of IL-33 cytokine activity, and its deletion has recently been shown to result in constitutive extracellular release of the protein, multiorgan inflammation, and death of the organism (44). The cleavage/activation domain is likely to represent another important domain for regulation of IL-33 biological activity in vivo.…”

Section: Discussionmentioning

confidence: 99%

Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells

Lefrançais

Duval

Mirey

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

321

310

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Interleukin-33 (IL-33) is an alarmin cytokine from the IL-1 family. IL-33 activates many immune cell types expressing the interleukin 1 receptor-like 1 (IL1RL1) receptor ST2, including group-2 innate lymphoid cells (ILC2s, natural helper cells, nuocytes), the major producers of IL-5 and IL-13 during type-2 innate immune responses and allergic airway inflammation. IL-33 is likely to play a critical role in asthma because the IL33 and ST2/IL1RL1 genes have been reproducibly identified as major susceptibility loci in large-scale genome-wide association studies. A better understanding of the mechanisms regulating IL-33 activity is thus urgently needed. Here, we investigated the role of mast cells, critical effector cells in allergic disorders, known to interact with ILC2s in vivo. We found that serine proteases secreted by activated mast cells (chymase and tryptase) generate mature forms of IL-33 with potent activity on ILC2s. The major forms produced by mast cell proteases, IL-33 95-270 , IL-33 107-270 , and IL-33 109-270 , were 30-fold more potent than full-length human IL-33 1-270 for activation of ILC2s ex vivo. They induced a strong expansion of ILC2s and eosinophils in vivo, associated with elevated concentrations of IL-5 and IL-13. Murine IL-33 is also cleaved by mast cell tryptase, and a tryptase inhibitor reduced IL-33-dependent allergic airway inflammation in vivo. Our study identifies the central cleavage/activation domain of IL-33 (amino acids 66-111) as an important functional domain of the protein and suggests that interference with IL-33 cleavage and activation by mast cell and other inflammatory proteases could be useful to reduce IL-33-mediated responses in allergic asthma and other inflammatory diseases.cytokine | IL-33 | allergic inflammation | mast cell protease | innate lymphoid cells

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Section: Discussionmentioning

confidence: 99%

Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells

Lefrançais

Duval

Mirey

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

321

310

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“…While promoting tissue eosinophilia by inducing cytokine generation from lymphoid cells (49,50), IL-33 can also induce full activation of MCs (37), including systemic anaphylaxis (31), when released in response to environmental danger signals. The fact that endogenous cysLTs were involved in the basal expression, release, and processing of IL-33 in the lungs of ptges −/− mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Aspirin Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway

Liu

Kanaoka

Barrett

et al. 2016

Journal of Allergy and Clinical Immunology

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Aspirin exacerbated respiratory disease (AERD), a severe eosinophilic inflammatory disorder of the airways, involves overproduction of cysteinyl leukotrienes (cysLTs), activation of airway mast cells (MCs), and bronchoconstriction in response to nonselective cyclooxygenase inhibitors that deplete homeostatic prostaglandin (PG)E 2 . The mechanistic basis for MC activation in this disorder is unknown. We now demonstrate that patients with AERD have markedly increased epithelial expression of the alarmin-like cytokine IL-33 in nasal polyps, as compared to polyps from aspirin tolerant (AT) controls. The murine model of AERD, generated by dust mite priming of mice lacking microsomal PGE 2 synthase (ptges −/− mice), shows a similar upregulation of IL-33 protein in the airway epithelium, along with marked eosinophilic bronchovascular inflammation. Deletion of LTC 4 synthase (LTC 4 S), the terminal enzyme needed to generate cysLTs, eliminates the increased IL-33 content of the ptges −/− lungs and sharply reduces pulmonary eosinophilia and basal secretion of MC products. Challenges of dust mite-primed ptges −/− mice with lysine aspirin (Lys-ASA) induce IL-33-dependent MC activation and bronchoconstriction. Thus, IL-33 is a component of a cysLT-driven innate type 2 immune response that drives pathogenic MC activation and contributes substantially to AERD pathogenesis.

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“…Additionally, cell injury or necrosis can also cause loss of nuclear IL-33 and mediate inflammation and some aspects of disease pathogenesis in vivo [51]. This is highlighted in mutant mice lacking IL-33 nuclear localisation signal which demonstrate severe non-resolving inflammation [51].…”

Section: Regulation Of Gene Expression By Il-33mentioning

confidence: 99%

“…This is highlighted in mutant mice lacking IL-33 nuclear localisation signal which demonstrate severe non-resolving inflammation [51]. nuclear IL-33 can modulate inflammation through actions on NF-B where it can both enhance basal and TNF-stimulated ICAM-1 and VCAM-1 expression [42] and attenuate NF-B activation and the expression of selected inflammatory genes [41].…”

Section: Regulation Of Gene Expression By Il-33mentioning

confidence: 99%

Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension

Shao

Perros

Caramori

et al. 2014

Biochemical and Biophysical Research Communications

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Altered subcellular localization of IL-33 leads to non-resolving lethal inflammation

Cited by 144 publications

References 50 publications

Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells

Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells

Aspirin Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway

Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension

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