Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells Elizabeth.

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Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells Elizabeth A. Oczypok, BS, Pavle S. Milutinovic, MD, PhD, John F. Alcorn, PhD, Anupriya Khare, PhD, Lauren T. Crum, BS, Michelle L. Manni, PhD, Michael W. Epperly, PhD, Adriane M. Pawluk, Anuradha Ray, PhD, Tim D. Oury, MD, PhD Journal of Allergy and Clinical Immunology Volume 136, Issue 3, Pages 747-756.e4 (September 2015) DOI: 10.1016/j.jaci.2015.03.011 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 IL-33 upregulation in response to HDM extract is dependent on RAGE expression. A and B, Immunoblot probing for IL-33 in whole lung homogenate after 7 weeks of HDM treatments (Fig 1, A) and summary of normalized IL-33/β-actin signal intensity ratios (saline control set arbitrarily to 1.0; Fig 1, B). C, Quantitative RT-PCR of whole lung homogenate RNA after 7 weeks of HDM treatments probing for IL-33. IL-33 signal was normalized to the glycerldehyde-3-phosphate dehydrogenase signal, and results are expressed as fold change over wild-type (WT) saline values. In all cases results are expressed as means ± SEMs (n = 3-6 mice per strain per treatment group). *P < .05 versus comparison. Journal of Allergy and Clinical Immunology 2015 136, 747-756.e4DOI: (10.1016/j.jaci.2015.03.011) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Absence of RAGE attenuates the cellular inflammatory and airway hyperreactivity responses to A alternata in an acute model of allergic airway disease. A and B, Representative hematoxylin and eosin (Fig 2, A) and periodic acid–Schiff (Fig 2, B) stains (×200 magnification) of wild-type (WT) and RAGE KO mouse lung sections. C, Bronchoalveolar lavage fluid total cell and eosinophil counts normalized to 1 mL. D, Pulmonary function test demonstrating changes in airway resistance (Rn) during methacholine challenge. All samples/functional analyses were collected on day 10. Results are expressed as means ± SEMs (n = 7-14 mice per strain per treatment group for Fig 2, A-C; n = 3-4 mice per group for pulmonary function tests). *P < .05 versus comparison. Journal of Allergy and Clinical Immunology 2015 136, 747-756.e4DOI: (10.1016/j.jaci.2015.03.011) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Absence of RAGE results in blunted IL-5, IL-13, and IL-33 cytokine responses to A alternata in an acute model of allergic airway disease. A and B, ELISA analyses of IL-5 and IL-13 levels in bronchoalveolar lavage fluid at day 10 in an A alternata model. C, Immunoblot probing for IL-33 in whole lung homogenate after 10-day A alternata treatment and summary of normalized IL-33/β-actin signal intensity ratios (saline controls set arbitrarily to 1.0; right). In all cases results are expressed as means ± SEMs (n = 7-14 mice per strain/treatment group). *P < .05 versus comparison. WT, Wild-type. Journal of Allergy and Clinical Immunology 2015 136, 747-756.e4DOI: (10.1016/j.jaci.2015.03.011) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Development of inflammatory effects in the lung downstream of exogenous IL-33 depends on RAGE. A and B, Representative hematoxylin and eosin (Fig 4, A) and periodic acid–Schiff (Fig 4, B) stains of lung sections (×200 magnification) from wild-type (WT) and RAGE KO mice after IL-33 administration. C, Bronchoalveolar lavage fluid total cell and eosinophil counts normalized to 1 mL. D, ELISA analyses of IL-5 and IL-13 levels in bronchoalveolar lavage fluid after treatment with rIL-33. All samples were collected after 4 days of IL-33 treatment. In all cases results are expressed as means ± SEMs (n = 3-11 mice per strain per treatment group). *P < .05 versus comparison. Journal of Allergy and Clinical Immunology 2015 136, 747-756.e4DOI: (10.1016/j.jaci.2015.03.011) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 RAGE is required for ILC2 accumulation in the lung. A, Representative flow plots of the live, lineage-negative cell populations gated for expression of CD90.2 and ST2. Numbers in each quadrant are percentages of the parent population. ILC2s were identified as lineage-negative cells that coexpress CD90.2 and ST2. B and C, Graphic summary of flow cytometrically enumerated ILC2s in one lung after 4 days of treatment with rIL-33 (Fig 5, B) or 10 days of treatment with A alternata (Fig 5, C). Results are expressed as means ± SEMs (n = 3-11 mice per strain per treatment group). *P < .05 versus comparison. WT, Wild-type. Journal of Allergy and Clinical Immunology 2015 136, 747-756.e4DOI: (10.1016/j.jaci.2015.03.011) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Stromal, but not hematopoietic, RAGE drives AAI. A and B, Bronchoalveolar lavage fluid total cell counts (Fig 6, A) and eosinophil counts (Fig 6, B) of bone marrow chimeric mice treated intranasally for 7 weeks with HDM extract or saline control. Treatment groups are labeled as recipient strain (bone marrow donor strain). In all cases results are expressed as means ± SEMs (n = 3-7 mice per strain per treatment group). *P < .05 versus comparison. BM, Bone marrow; ns, not significant; WT, wild-type. Journal of Allergy and Clinical Immunology 2015 136, 747-756.e4DOI: (10.1016/j.jaci.2015.03.011) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 RAGE is not required for ILC2 induction, proliferation, or secretory function in the alimentary tract after intraperitoneal rIL-33 administration. A, Immunoblot probing for RAGE in mouse whole-organ homogenates. B, Representative periodic acid–Schiff stains of mouse ileum sections (×100 magnification). C, IL-5 and IL-13 levels in peritoneal lavage fluid. D, Representative lung sections stained with hematoxylin and eosin (×100 magnification). E, ILC2 (Lin−, CD90.2+, ST2+) counts in the spleen. All samples were collected after 3 days of IL-33 injection. Results are expressed as means ± SEMs (n = 3-5 mice per strain per treatment group). *P < .05 versus comparison. WT, Wild-type. Journal of Allergy and Clinical Immunology 2015 136, 747-756.e4DOI: (10.1016/j.jaci.2015.03.011) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Models of AAI. A, Chronic HDM model. B, Acute A alternata model. C, Intranasal recombinant IL-33 model. D, Intraperitoneal IL-33 model. i.n., Intranasal; i.p., intraperitoneal. Journal of Allergy and Clinical Immunology 2015 136, 747-756.e4DOI: (10.1016/j.jaci.2015.03.011) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 TSLP and IL-25 expression are not dependent on RAGE expression in the lung. A, There is no significant difference in TSLP expression in whole-lung homogenates after 7 weeks of HDM treatment between any of the strain or treatment groups. B, In contrast, IL-25 secretion in the bronchoalveolar lavage fluid after 7 weeks of HDM exposure is upregulated in response to allergen in both wild-type (WT) and RAGE KO mice but is inadequate to precipitate a type 2 immune response in RAGE KO mice at the levels observed in this disease model.20 Results are expressed as means ± SEMs (n = 3-6 mice per strain per treatment group). *P < .05 versus comparison. ns, Not significant. Journal of Allergy and Clinical Immunology 2015 136, 747-756.e4DOI: (10.1016/j.jaci.2015.03.011) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Gating strategy for lung and spleen ILC2s. A, Gating strategy for lung ILC2s (used for both IL-33 intranasal and A alternata experiments). B, Gating strategy for spleen ILC2s after IL-33 administered intraperitoneally. In both organs live (green) lineage-negative (blue) cells were selected and analyzed for coexpression of the surface markers CD90.2 and ST2 (red). SSC, Side scatter. Journal of Allergy and Clinical Immunology 2015 136, 747-756.e4DOI: (10.1016/j.jaci.2015.03.011) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Numbers of CD4+ T cells expressing IL-5 and IL-13 are not increased in RAGE KO mice in response to allergen. A and B, CD4+IL-5+ cells (Fig E4, A) and CD4+IL-13+ cells (Fig E4, B) are increased in wild-type (WT) mice after 10-day A alternata treatment but are not increased in RAGE KO mice. Results are expressed as means ± SEMs (n = 3-5 mice per strain per treatment group). *P < .05 versus comparison. Journal of Allergy and Clinical Immunology 2015 136, 747-756.e4DOI: (10.1016/j.jaci.2015.03.011) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions