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IL-33 induces innate lymphoid cell–mediated airway inflammation by activating mammalian target of rapamycin  Robert J. Salmond, PhD, Ananda S. Mirchandani,

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Presentation on theme: "IL-33 induces innate lymphoid cell–mediated airway inflammation by activating mammalian target of rapamycin  Robert J. Salmond, PhD, Ananda S. Mirchandani,"— Presentation transcript:

1 IL-33 induces innate lymphoid cell–mediated airway inflammation by activating mammalian target of rapamycin  Robert J. Salmond, PhD, Ananda S. Mirchandani, MBChB, Anne-Gaelle Besnard, PhD, Calum C. Bain, BSc, Neil C. Thomson, MD, Foo Y. Liew, PhD  Journal of Allergy and Clinical Immunology  Volume 130, Issue 5, Pages e6 (November 2012) DOI: /j.jaci Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 IL-33 induces mTOR activation in TH2 cells. A and B, Histograms show phospho-rpS6 in D10.G4.1 or WT and St2−/− TH2 cells. CM, Complete medium. C and D, Time course and dose response of IL-33–induced rpS6 phosphorylation in D10.G4.1 cells. E, Western blots of phospho-Akt and S6K1. F, Relative levels of phospho-rpS6 in D10.G4.1 cells after stimulation with IL-33 in the presence of no inhibitor (NI), rapamycin (Rap.; 100 nmol/L), IC87114 (IC; 5 μmol/L), or PF (S6K1i; 10 μmol/L). Error bars represent SDs (n = 4). Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 mTOR regulates IL-33–induced cytokine production. Effects of rapamycin (Rap.; 100 nmol/L) on levels of IL-5 (A) and IL-13 (B) induced by IL-33 ± IL-2. CM, Complete medium. ∗P < .05 and ∗∗∗P < .001, unpaired Student t test). Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 PI3K p110δ and S6K1 inhibitors reduce IL-33–induced IL-13 production. A, Comparison of the effects of rapamycin (Rap.; 100 nmol/L), IC87114 (5 μmol/L), and PF (S6K1i; 10 μmol/L) on levels of IL-33–induced IL-13 produced by TH2 cells. Error bars represent SDs (n = 3-12). Data represent one of 3 repeated experiments. CM, Complete medium. ∗∗∗P < .001, unpaired Student t test. B, Schematic representation of the role of the mTOR pathway in IL-33–induced cytokine production. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Rapamycin reduces IL-33–induced airway inflammation. A, Effect of rapamycin (Rap; 1 mg/kg) on IL-33–induced total BAL cell, eosinophil, and macrophage accumulation. Values are from individual mice, and bars represent means. B, Levels of IL-5 and IL-13 in BAL fluid. C, Histologic analysis of lung sections after hematoxylin and eosin (HE) or periodic acid–Schiff (PAS) staining. Scale bars = 200 μm. Data are representative of 3 to 8 mice per group. D, Histologic scores of cell infiltration and mucus deposition. Error bars represent SEMs. ∗P < .05, ∗∗P < .01, and ∗∗∗P < 0.001, unpaired Student t test. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 Type 2 ILCs are the predominant cytokine-producing population induced by IL-33 in murine lungs, whereas rapamycin (Rap) reduces their accumulation. A, Fluorescence-activated cell sorting analysis of IL-5–producing cells present in lung digests. B, Effects of rapamycin on total ILCs, IL-5–producing ILCs, and IL-13–producing ILCs. ∗P < .05, unpaired Student t test. Error bars represent SDs (n = 3-4 per group), and data represent one of 3 repeated experiments. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 Rapamycin (Rap) directly inhibits ILC effector function. A, Western blots for phospho-rpS6 in ILCs. Data represent one of 4 experiments. B and C, Effect of rapamycin (100 nmol/L) on IL-5 and IL-13 induced by IL-33 (Fig 6, B) or IL-33 ± TSLP or IL-7 (Fig 6, C). D, Effect of rapamycin on IL-33–induced Il13 mRNA levels. Data represent one of 3 experiments. E, Effect of rapamycin on ILC proliferation induced by IL-33 ± TSLP or IL-7. All error bars represent SDs (n = 3), and all data represent one of at least 3 repeated experiments. CM, Complete medium. ∗ P < .05 and ∗∗∗P < .001, Student t test. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig 7 ILCs are sufficient to mediate IL-33–induced airway inflammation. A, Cell counts in BAL fluid and lung digests from IL-33–treated St2−/− mice receiving WT ILCs. B, Levels of IL-5 and IL-13 in BAL fluid. Values represent means ± SDs of 3 to 4 mice. C, Histologic scores of lung sections. Error bars represent SEMs (n = 7-8). ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig 8 Rapamycin (Rap) inhibits ILC-induced airway inflammation. A, Cell numbers in BAL fluid and lung digests. Horizontal bars represent means, and data represent values from individual mice (4-5 per group) from one of 3 repeated experiments. B, Eosinophil, macrophage, neutrophil, and donor ILC cell numbers in lung digests. C, Levels of IL-33–induced, ILC-dependent IL-5 and IL-13 in BAL fluid. Error bars represent SDs (n = 4-5). ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001, all unpaired Student t test. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Fig E1 Efficacy and specificity of pharmacologic inhibitors. A, Effects of IC87114 (IC; 5 μmol/L) and S6K1 inhibitor (S6K1i; 10 μmol/L) on IκBα degradation, p38, and Akt phosphorylation. B and C, Effects of rapamycin (Rap; 100 nmol/L) and Torin-1 (Tor1; 100 nmol/L) on IL-33–induced S6K1, rpS6, and Akt phosphorylation (Fig E1, B) and p38 activation and IκBα degradation (Fig E1, C). D, Dose-response effects of rapamycin on IL-33–induced rpS6 phosphorylation. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Fig E2 Rapamycin inhibits the effects of IL-33 on TCR-induced differentiation. Naive T cells were stimulated with CD3 and CD28 in the presence or absence of IL-33 and rapamycin (100 nmol/L). Levels of IL-5 (A) and IL-13 (B) in supernatants were assessed by means of ELISA. Error bars represent SEMs (n = 3). Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

12 Fig E3 Rapamycin inhibits IL-13 protein production independently of effects on Il13 mRNA or HuR expression. A and B, Bar charts show levels of Il13 mRNA expression in TH2 cells (Fig E3, A) or protein in supernatants (Fig E3, B) after stimulation with IL-33 + IL-2 ± rapamcycin (Rap; 100 nmol/L). Data depict values from 1 of 3 repeated experiments, and error bars represent SDs (n = 2). C, Western blot showing levels of HuR expression in TH2 cells stimulated as described above. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

13 Fig E4 Phenotypic analysis of type 2 ILCs. A, Fluorescence-activated cell sorting analysis demonstrating IL-33–elicited IL-13–producing cells present in lung digests are predominantly Lin−CD45+ICOS+ST2+ ILCs. B, Dot plots depict proportions of gated CD45+Lin− type 2 ILCs before and after cell sorting, as assessed by analysis of ST2 and ICOS expression. C, Histograms showing cell-surface expression of CD11c, NK1.1, TCRγδ, TCRβ, CD25, CD127, and c-Kit on purified type 2 ILCs. Shaded histograms represent isotype controls. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

14 Fig E5 Transferred WT ILCs facilitate IL-33–induced inflammation in St2−/− recipients. A, Eosinophil, macrophage, neutrophil, and donor ILC numbers in BAL fluid and lung digests from IL-33–treated St2−/− mice receiving WT ILCs. Horizontal bars represent means, and data represent individual animals from 2 pooled experiments. B, Histologic analysis of lung sections stained with hematoxylin and eosin (HE) and periodic acid–Schiff (PAS). Pictures depict representative fields from 1 of 7 to 8 mice per group. Scale bars = 200 μm. ∗P < .05 and ∗∗P < .01. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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