MicroRNA-155 is a critical regulator of type 2 innate lymphoid cells and IL-33 signaling in experimental models of allergic airway inflammation Kristina.

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MicroRNA-155 is a critical regulator of type 2 innate lymphoid cells and IL-33 signaling in experimental models of allergic airway inflammation Kristina Johansson, MSc, Carina Malmhäll, PhD, Patricia Ramos-Ramírez, PhD, Madeleine Rådinger, PhD Journal of Allergy and Clinical Immunology Volume 139, Issue 3, Pages 1007-1016.e9 (March 2017) DOI: 10.1016/j.jaci.2016.06.035 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 miR-155−/− mice exhibit reduced eosinophilic inflammation and subepithelial collagen deposition in response to chronic allergen challenge. Experimental models of acute (A) or chronic (B) OVA-induced allergic airway inflammation. C and D, Total cells in BALF. Lung sections stained with Masson's trichrome stain (E) and hematoxylin and eosin (F). G, Collagen thickness around airway epithelium. H, miR-155 expression in lungs of OVA-challenged mice compared with PBS-treated mice. Fig 1, E-H, refer to chronic OVA model. BALF, Bronchoalveolar lavage fluid; Eos, eosinophil; i.n., intranasal; i.p., intraperitoneal; Lym, lymphocyte; Mac, macrophage; Neu, neutrophil; ns, nonsignificant. Data are shown as means ± SEM (n = 4-8 per group). *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2017 139, 1007-1016.e9DOI: (10.1016/j.jaci.2016.06.035) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Lack of miR-155 alters ST2/IL33R expression on ILC2s and impairs lung IL-33 production in response to acute or chronic allergen challenge. A and E, Total number of lung ILC2s. B and F, IL-33 protein levels in lungs. C and G, ST2 expression on lung ILC2s (Lin−CD45+CD127+CD25+). D and H, Fold regulation of ST2 MFI on ILC2s from OVA-challenged mice compared with PBS-treated mice. Fig 2, A-D, refer to the acute OVA model and E-H refer to the chronic OVA model. FMO, Fluorescence minus one; MFI, mean fluorescent intensity. Data are shown as means ± SEM (n = 5-8 per group). *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2017 139, 1007-1016.e9DOI: (10.1016/j.jaci.2016.06.035) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 miR-155 is crucial for IL-33–induced eosinophilic inflammation and ILC2 expansion. A, Experimental model of IL-33–induced airway inflammation. B, Total cells in BALF. C, May Grünwald-Giemsa–stained BALF cells from IL-33–challenged mice. D, Total number of lung ILC2s. E, ST2 expression on lung ILC2s (Lin−CD45+CD127+CD25+). F, Fold regulation of ST2 MFI on ILC2s from IL-33–challenged mice compared with PBS-treated mice. BALF, Bronchoalveolar lavage fluid; FMO, Fluorescence minus one; MFI, mean fluorescent intensity; ns, nonsignificant. Data are shown as means ± SEM (n = 4-6 per group). *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2017 139, 1007-1016.e9DOI: (10.1016/j.jaci.2016.06.035) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 miR-155−/− ILC2s exhibit impaired proliferation and GATA-3 and ICOS expression in response to intranasal IL-33 challenge. A, Ki-67+ Lin− lung cells. B, Percentage proliferating (Ki-67+) Lin− cells of CD45+ mononuclear lung cells. C, Percentage GATA-3+, ICOS+, and ST2+ proliferating Lin− cells of IL-33–challenged mice. D, GATA-3+ Lin− lung cells. E, Percentage GATA-3+ Lin− cells of CD45+ mononuclear lung cells. Data are shown as means ± SEM (n = 3-7 per group). *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2017 139, 1007-1016.e9DOI: (10.1016/j.jaci.2016.06.035) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 miR-155−/− ILC2s exhibit impaired IL-13 production but not IL-5 in response to intranasal IL-33 challenge. A, Lin−ST2+ lung cells. B, Percentage Lin−ST2+ cells of CD45+ mononuclear cells. Percentage IL-13+ (C) and IL-5+ (D) cells of Lin−ST2+ lung cells. E, IL-13 or IL-5 expression in lung ILC2s (Lin−CD45+ST2+). FMO, Fluorescence minus one. Data are shown as means ± SEM (n = 5-7 per group). *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2017 139, 1007-1016.e9DOI: (10.1016/j.jaci.2016.06.035) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 ILC2s upregulate miR-155 expression in response to IL-33 stimulation in vitro. A, Sorting strategy of lung ILC2s (Lin−CD45+CD25+ICOS+ST2+). B, Sorted ILC2s stained with Hemacolor rapid stain. C, Receptor MFI (ICOS/CD25/ST2) on in vitro unstimulated or IL-33–stimulated ILC2s. D, miR-155 expression in in vitro IL-33–stimulated ILC2s compared with unstimulated ILC2s. Data are shown as means ± SEM (n = 3-5 per group). MFI, Mean fluorescent intensity. **P < .01. Journal of Allergy and Clinical Immunology 2017 139, 1007-1016.e9DOI: (10.1016/j.jaci.2016.06.035) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Total cells in BALF from acute OVA (A), chronic OVA (B), or IL-33–challenged (C) WT and miR-155−/− mice and PBS control mice. Eos, Eosinophil; Neu, neutrophil; Lym, lymphocyte; Mac, macrophage; ns, nonsignificant. Data are shown as means ± SEM (n = 4-8 per group). *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2017 139, 1007-1016.e9DOI: (10.1016/j.jaci.2016.06.035) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 A, Gating strategy of lung ILC2s (Lin−CD45+CD127+CD25+). B, Total number of lung ILC2s. C, Percentage ILC2s of all leukocytes (CD45+). D, Percentage CD127+ (IL7Rα) cells of Lin−CD45+ mononuclear lung cells. E, Percentage CD25+(IL2Rα), ICOS+, and ST2+ (IL33 R) cells of Lin−CD45+CD127+ cells. F, CD25, ICOS, and ST2 expression on Lin−CD45+CD127+ cells. Lungs from naive WT and miR-155−/− mice are analyzed in Fig E2, B-F. FMO, Fluorescence minus one; FSC-A, forward-scatter area; FSC-H, forward-scatter height; SSC-A, side-scatter area. Data are shown as means ± SEM (n = 4 per group). Journal of Allergy and Clinical Immunology 2017 139, 1007-1016.e9DOI: (10.1016/j.jaci.2016.06.035) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Scatter graph demonstrating correlation analysis between BALF eosinophils (Eos; mL−1 BALF) and total lung ILC2s of acute OVA (A), chronic OVA (B), or IL-33–challenged (C) WT and miR-155−/− mice and PBS control mice. Eos, Eosinophils; rs, Spearman correlation coefficient. Data are shown as means ± SEM (n = 4-8 per group). Journal of Allergy and Clinical Immunology 2017 139, 1007-1016.e9DOI: (10.1016/j.jaci.2016.06.035) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 A, Gating strategy of lung T helper cells (CD45+CD3+CD4+). Percent CD4+ T helper cells of all T cells (B) (CD45+CD3+) and CD25+ CD4+ T helper cells (C) in lungs from chronic allergen-challenged WT and miR-155−/− mice and PBS control mice. FSC-A, Forward-scatter area; FSC-H, forward-scatter height; SSC-A, side-scatter area. Data are shown as means ± SEM (n = 5-8 per group). Journal of Allergy and Clinical Immunology 2017 139, 1007-1016.e9DOI: (10.1016/j.jaci.2016.06.035) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Scatter graph demonstrating correlation analysis between BALF eosinophils (Eos; mL−1 BALF) and lung IL-33 (pg/mg lung) of acute (A) and chronic (B) OVA-challenged WT and miR-155−/− mice and PBS control mice. Eos, Eosinophils; rs, Spearman correlation coefficient. Data are shown as means ± SEM (n = 5-8 per group). Journal of Allergy and Clinical Immunology 2017 139, 1007-1016.e9DOI: (10.1016/j.jaci.2016.06.035) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Scatter graph demonstrating correlation analysis between ST2 (relative mean fluorescent index; rMFI) on lung ILC2s and IL-33 (pg/mg lung) of acute (A) and chronic (B) OVA-challenged WT and miR-155−/− mice and PBS control mice. rs, Spearman correlation coefficient. Data are shown as means ± SEM (n = 5-8 per group). Journal of Allergy and Clinical Immunology 2017 139, 1007-1016.e9DOI: (10.1016/j.jaci.2016.06.035) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions