Environmental allergens induce allergic inflammation through proteolytic maturation of IL-33

Cayrol, Corinne; Duval, Alex; Schmitt, Pauline; Roga, Stéphane; Camus, Mylène; Stella, Alexandre; Burlet‐Schiltz, Odile; Peredo, Anne Gonzalez de; Girard, Jean-Philippe

doi:10.1038/s41590-018-0067-5

Cited by 278 publications

(245 citation statements)

References 53 publications

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“…Here, for the first time to our knowledge, we presented the complementary phenomenon, in which the mouse IL‐33 activates human basophils. Of note, mouse IL‐33 was found to undergo a rapid degradation following cleavage while the human cleaved product remains stable .…”

Section: Discussionmentioning

confidence: 99%

Necroptosis directly induces the release of full‐length biologically active IL‐33 in vitro and in an inflammatory disease model

et al. 2019

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Interleukin‐33 (IL‐33) is a pro‐inflammatory cytokine that plays a significant role in inflammatory diseases by activating immune cells to induce type 2 immune responses upon its release. Although IL‐33 is known to be released during tissue damage, its exact release mechanism is not yet fully understood. Previously, we have shown that cleaved IL‐33 can be detected in the plasma and epithelium of Ripk1−/− neonates, which succumb to systemic inflammation driven by spontaneous receptor‐interacting protein kinase‐3 (RIPK3)‐dependent necroptotic cell death, shortly after birth. Thus, we hypothesized that necroptosis, a RIPK3/mixed lineage kinase‐like protein (MLKL)‐dependent, caspase‐independent cell death pathway controls IL‐33 release. Here, we show that necroptosis directly induces the release of nuclear IL‐33 in its full‐length form. Unlike the necroptosis executioner protein, MLKL, which was released in its active phosphorylated form in extracellular vesicles, IL‐33 was released directly into the supernatant. Importantly, full‐length IL‐33 released in response to necroptosis was found to be bioactive, as it was able to activate basophils and eosinophils. Finally, the human and murine necroptosis inhibitor, GW806742X, blocked necroptosis and IL‐33 release in vitro and reduced eosinophilia in Aspergillus fumigatus extract‐induced asthma in vivo, an allergic inflammation model that is highly dependent on IL‐33. Collectively, these data establish for the first time, necroptosis as a direct mechanism for IL‐33 release, a finding that may have major implications in type 2 immune responses.

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Section: Discussionmentioning

confidence: 99%

Necroptosis directly induces the release of full‐length biologically active IL‐33 in vitro and in an inflammatory disease model

et al. 2019

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“…After cell injury or cellular activation through ATP signaling, these cells promptly release IL‐33; moreover, under certain conditions, NKT cells and alveolar macrophages might also constitute sources of IL‐33 . Released full‐length IL‐33 is rapidly cleaved by protease derived from neutrophils, mast cells, or an environmental allergen itself, with the mature form of IL‐33 being 30‐fold more potent for activation of ILC2s than the full‐length IL‐33 . IL‐33 binds to a heterodimeric receptor formed by T1/ST2 and the IL‐1 receptor accessory protein (IL‐1RAcP), which leads to activation of NF‐κB and MAPK (ERK, p38, JNK) signaling pathways via MyD88 .…”

Section: Activating Cytokines (Il‐33 and Il‐25)mentioning

confidence: 99%

The group 2 innate lymphoid cell (ILC2) regulatory network and its underlying mechanisms

Kabata

Moro

Koyasu

2018

Immunological Reviews

229

183

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Summary Group 2 innate lymphoid cells (ILC2s) play critical roles in the induction of type 2 inflammation, response to parasite infection, metabolic homeostasis, and tissue repair. These multifunctional roles of ILC2s are tightly controlled by complex regulatory systems in the local microenvironment, the disruption of which may cause various health problems. This review summarizes up‐to‐date knowledge regarding positive and negative regulators for ILC2s based on their function and signaling pathways, including activating cytokines (IL‐33, IL‐25; MAPK, NF‐κB pathways), co‐stimulatory cytokines (IL‐2, IL‐7, IL‐9, TSLP; STAT5, IL‐4; STAT6, TNF superfamily; MAPK, NF‐κB pathways), suppressive cytokines (type1 IFNs, IFN‐γ, IL‐27; STAT1, IL‐10, TGF‐β), transdifferentiation cytokines (IL‐12; STAT4, IL‐1β, IL‐18), lipid mediators (LTC4, LTD4, LTE4, PGD2; Ca2+‐NFAT pathways, PGE2, PGI2; AC/cAMP/PKA pathways, LXA4, LTB4), neuropeptides (NMU; Ca2+‐NFAT, MAPK pathways, VIP, CGRP, catecholamine, acetylcholine), sex hormones (androgen, estrogen), nutrients (butyrate; HDAC inhibitors, vitamins), and cell‐to‐cell interactions (ICOSL‐ICOS; STAT5, B7‐H6‐NKp30, E‐cadherin‐KLRG1). This comprehensive review affords a better understanding of the regulatory network system for ILC2s, providing impetus to develop new treatment strategies for ILC2‐related health problems.

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“…15,18,26 This notion is also borne out in our results using the CXCR2 inhibitor DF2156A, which significantly but not completely reversed IL-33-mediated mortality and weight loss in the DENV2infected mice. 33,34 Our analysis was carried out on days 4 and 6 after infection. Previous studies have shown that IL-33 directly increases CD69 expression in CD8 + T cells and NK cells, and enhances IFN-c production by NK cells.…”

Section: Discussionmentioning

confidence: 99%

“…34,37 Hence, the deleterious effect of IL-33 in dengue infection whose pathology is chiefly mediated by Th1-type of response is counter-intuitive. 34,37 Hence, the deleterious effect of IL-33 in dengue infection whose pathology is chiefly mediated by Th1-type of response is counter-intuitive.…”

Section: Discussionmentioning

confidence: 99%

“…This is consistent with the accepted concept that IL-33 is an important alarmin. 33,34 Our analysis was carried out on days 4 and 6 after infection. The effect of the CD8 + T cells and NK cells could manifest in an even more pronounced fashion at a later phase of the infection 35,36 , a hypothesis that merits to be investigated using a less severe model of DENV2 infection.…”

Section: Discussionmentioning

confidence: 99%

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Interleukin‐33 contributes to disease severity in Dengue virus infection in mice

Marques

Besnard²,

Maillet

et al. 2018

Immunology

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The excessive inflammation often present in patients with severe dengue infection is considered both a hallmark of disease and a target for potential treatments. Interleukin-33 (IL-33) is a pleiotropic cytokine with pro-inflammatory effects whose role in dengue has not been fully elucidated. We demonstrate that IL-33 plays a disease-exacerbating role during experimental dengue infection in immunocompetent mice. Mice infected with dengue virus serotype 2 (DENV2) produced high levels of IL-33. DENV2-infected mice treated with recombinant IL-33 developed markedly more severe disease compared with untreated mice as assessed by mortality, granulocytosis, liver damage and pro-inflammatory cytokine production. Conversely, ST2 mice (deficient in IL-33 receptor) infected with DENV2 developed significantly less severe disease compared with wild-type mice. Furthermore, the increased disease severity and the accompanying pathology induced by IL-33 during dengue infection were reversed by the simultaneous treatment with a CXCR2 receptor antagonist (DF2156A). Together, these results indicate that IL-33 plays a disease-exacerbating role in experimental dengue infection, probably driven by CXCR2-expressing cells, leading to elevated pro-inflammatory response-mediated pathology. Our results also indicate that IL-33 is a potential therapeutic target for dengue infection.

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Environmental allergens induce allergic inflammation through proteolytic maturation of IL-33

Cited by 278 publications

References 53 publications

Necroptosis directly induces the release of full‐length biologically active IL‐33 in vitro and in an inflammatory disease model

Necroptosis directly induces the release of full‐length biologically active IL‐33 in vitro and in an inflammatory disease model

The group 2 innate lymphoid cell (ILC2) regulatory network and its underlying mechanisms

Interleukin‐33 contributes to disease severity in Dengue virus infection in mice

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