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The Innate Cytokines IL-25, IL-33, and TSLP Cooperate in the Induction of Type 2 Innate Lymphoid Cell Expansion and Mucous Metaplasia in Rhinovirus-Infected Immature Mice.

ABSTRACT: Early-life respiratory viral infection is a risk factor for asthma development. Rhinovirus (RV) infection of 6-d-old mice, but not mature mice, causes mucous metaplasia and airway hyperresponsiveness that are associated with the expansion of lung type 2 innate lymphoid cells (ILC2s) and are dependent on IL-13 and the innate cytokine IL-25. However, contributions of the other innate cytokines, IL-33 and thymic stromal lymphopoietin (TSLP), to the observed asthma-like phenotype have not been examined. We reasoned that IL-33 and TSLP expression are also induced by RV infection in immature mice and are required for maximum ILC2 expansion and mucous metaplasia. We inoculated 6-d-old BALB/c (wild-type) and TSLP receptor-knockout mice with sham HeLa cell lysate or RV. Selected mice were treated with neutralizing Abs to IL-33 or recombinant IL-33, IL-25, or TSLP. ILC2s were isolated from RV-infected immature mice and treated with innate cytokines ex vivo. RV infection of 6-d-old mice increased IL-33 and TSLP protein abundance. TSLP expression was localized to the airway epithelium, whereas IL-33 was expressed in epithelial and subepithelial cells. RV-induced mucous metaplasia, ILC2 expansion, airway hyperresponsiveness, and epithelial cell IL-25 expression were attenuated by anti-IL-33 treatment and in TSLP receptor-knockout mice. Administration of intranasal IL-33 and TSLP was sufficient for mucous metaplasia. Finally, TSLP was required for maximal ILC2 gene expression in response to IL-25 and IL-33. The generation of mucous metaplasia in immature RV-infected mice involves a complex interplay among the innate cytokines IL-25, IL-33, and TSLP.

SUBMITTER: Han M

PROVIDER: S-EPMC5548608 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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The Innate Cytokines IL-25, IL-33, and TSLP Cooperate in the Induction of Type 2 Innate Lymphoid Cell Expansion and Mucous Metaplasia in Rhinovirus-Infected Immature Mice.

Han Mingyuan M Rajput Charu C Hong Jun Y JY Lei Jing J Hinde Joanna L JL Wu Qian Q Bentley J Kelley JK Hershenson Marc B MB

Journal of immunology (Baltimore, Md. : 1950) 20170712 4

Early-life respiratory viral infection is a risk factor for asthma development. Rhinovirus (RV) infection of 6-d-old mice, but not mature mice, causes mucous metaplasia and airway hyperresponsiveness that are associated with the expansion of lung type 2 innate lymphoid cells (ILC2s) and are dependent on IL-13 and the innate cytokine IL-25. However, contributions of the other innate cytokines, IL-33 and thymic stromal lymphopoietin (TSLP), to the observed asthma-like phenotype have not been exami ...[more]

PMID: 28701507

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Project description:Rationale: The major cause of heart failure is myocardium death consequent to detrimental cardiac remodeling and fibrosis following myocardial infarction. The cardiac protective cytokine interleukin (IL)-33, which signals by ST2 receptor binding, is associated with group 2 innate lymphoid cell (ILC2) activation and regulates tissue homeostasis and repair following tissue injury in various tissues. However, the distribution and role of IL-33-responsive ILC2s in cardiac fibrosis remain unclear. In this study, we elucidated the roles of IL-33-responsive cardiac-resident ILC2s and IL-33-mediated immunomodulatory functions in cardiac fibrosis. Methods: We examined the distribution of cardiac ILC2s by using flow cytometry. The roles of IL-33-mediated ILC2 expansion in cardiac fibrosis was evaluated in the mouse model of catecholamine-induced cardiac fibrosis. ILC-deficient Rag2‒/‒IL2Rγc‒/‒ mice were implemented to determine the contribution of endogenous ILC in the progression of cardiac fibrosis. Histopathological assessments, speckle tracking echocardiography, and transcriptome profile analysis were performed to determine the effects of IL-33-mediated cardiac protective functions. Results: We identified the resident cardiac ILC2s, which share similar cell surface marker and transcriptional factor expression characteristics as peripheral blood and lung tissue ILC2s. IL-33 treatment induced ILC2 expansion via ST2. In vivo, ILC-deficient Rag2‒/‒IL2Rγc‒/‒ mice developed exacerbated cardiac fibrosis following catecholamine-induced stress cardiac injury. IL-33 treatment expanded cardiac ILC2s and revealed protective effects against cardiac tissue damage with reduced cardiomyocyte death, immune cell infiltration, tissue fibrosis, and improved myocardial function. Transcriptome analysis revealed that IL-33 attenuated extracellular matrix synthesis- and fibroblast activation-associated gene expressions. IL13-knockout or epidermal growth factor receptor (EGFR) inhibition abolished IL-33-mediated cardiac protective function, confirming IL-13 and EGFR signaling as crucial for IL-33-mediated cardioprotective responses. Moreover, ILC2-produced BMP-7 served as a novel anti-fibrotic factor to inhibit TGF-β1-induced cardiac fibroblast activation. Conclusion: Our findings indicate the presence of IL-33-responsive ILC2s in cardiac tissue and that IL-33-mediated ILC2 expansion affords optimal cardioprotective function via ILC2-derived factors. IL-33-mediated immunomodulation is thus a promising strategy to promote tissue repair and alleviate cardiac fibrosis following acute cardiac injury.

Dataset Information

The Innate Cytokines IL-25, IL-33, and TSLP Cooperate in the Induction of Type 2 Innate Lymphoid Cell Expansion and Mucous Metaplasia in Rhinovirus-Infected Immature Mice.

Publications

The Innate Cytokines IL-25, IL-33, and TSLP Cooperate in the Induction of Type 2 Innate Lymphoid Cell Expansion and Mucous Metaplasia in Rhinovirus-Infected Immature Mice.

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