Exaggerated IL-17 response to epicutaneous sensitization mediates airway inflammation in the absence of IL-4 and IL-13 Rui He, MD, PhD, Hye Young Kim,

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Exaggerated IL-17 response to epicutaneous sensitization mediates airway inflammation in the absence of IL-4 and IL-13 Rui He, MD, PhD, Hye Young Kim, PhD, Juhan Yoon, PhD, Michiko K. Oyoshi, PhD, Andrew MacGinnitie, MD, Sho Goya, MD, PhD, Eva-Jasmin Freyschmidt, PhD, Paul Bryce, PhD, Andrew N.J. McKenzie, PhD, Dale T. Umetsu, MD, PhD, Hans C. Oettgen, MD, PhD, Raif S. Geha, MD Journal of Allergy and Clinical Immunology Volume 124, Issue 4, Pages 761-770.e1 (October 2009) DOI: 10.1016/j.jaci.2009.07.040 Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Exaggerated systemic TH17 responses in DKO mice epicutaneously sensitized with OVA. A, IL-17A and IFN-γ secretion by OVA-stimulated splenocytes and cells from skin DLNs. B, Intracellular IL-17A and IFN-γ staining of CD4+ cells in cultures of OVA-stimulated splenocytes. Data are representative of 3 experiments. C, Serum levels of IL-17A. Columns and error bars represent means and SEMs (n=5-7 per group). ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001. SAL, Saline; NS, not significant. Journal of Allergy and Clinical Immunology 2009 124, 761-770.e1DOI: (10.1016/j.jaci.2009.07.040) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Skin inflammation in epicutaneously sensitized DKO mice lacks eosinophils. A, Representative photomicrographs of hematoxylin and eosin–stained skin sections from sensitized sites at 200× magnification. B and C, Numbers of CD4+ cells (Fig 2, B) and eosinophils (Fig 2, C) were counted in a 400× high-power field. D, Expression of cytokine mRNA in sensitized skin. Columns and error bars represent means and SEMs (n=5-7 per group). ∗∗P < .01 and ∗∗∗P < .001. SAL, Saline; NS, not significant; N.D., not done. Journal of Allergy and Clinical Immunology 2009 124, 761-770.e1DOI: (10.1016/j.jaci.2009.07.040) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 DKO mice epicutaneously sensitized with OVA exhibit markedly increased expression of IL-17 and CXCL2 in the lungs after airway challenge with allergen. A and B, mRNA expression of cytokines. C, IL-17A protein secretion by OVA-stimulated lung cells. D, mRNA expression of chemokines. Columns and error bars represent means and SEMs (n=5-7 per group). ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001. SAL, Saline; N.D., not done. Journal of Allergy and Clinical Immunology 2009 124, 761-770.e1DOI: (10.1016/j.jaci.2009.07.040) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 DKO mice epicutaneously sensitized with OVA have airway inflammation and AHR after airway challenge with allergen. A, Total and differential counts in BALF. B and C, Representative photomicrographs of lung sections stained with hematoxylin and eosin (Fig 4, B) and PAS (Fig 4, C) at 200× magnification. The inset in Fig 4, B, shows the presence of eosinophils in WT but not DKO lungs. D and E, Penh response (Fig 4, D) and lung resistance (RL) and dynamic compliance (Cdyn) measurements (Fig 4, E). Columns or points and error bars represent means and SEMs (n=5-7 per group). ∗∗P < .01 and ∗∗∗P < .001. SAL, Saline; Mac, macrophages; Eos, eosinophils; Neu, neutrophils; Lym, lymphocytes. Journal of Allergy and Clinical Immunology 2009 124, 761-770.e1DOI: (10.1016/j.jaci.2009.07.040) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Blockade of IL-17A in vivo inhibits airway inflammation and methacholine hyperresponsiveness in epicutaneously (EC) sensitized DKO mice challenged with OVA. A, Total and differential counts in BALF. B, mRNA expression of CXCL2. C, Representative photomicrographs of lung sections stained with hematoxylin and eosin and examined at 200× magnification. D, Penh response to methacholine. Columns or points and error bars represent means and SEMs (n = 5-7 per group). ∗P < .05, ∗∗P < .01, and ∗∗∗P < .0001. SAL, Saline; Mac, macrophages; Eos, eosinophils; Neu, neutrophils; Lym, lymphocytes; Ctrl., control. Journal of Allergy and Clinical Immunology 2009 124, 761-770.e1DOI: (10.1016/j.jaci.2009.07.040) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 DKO mice mount a weaker IL-17 response to intraperitoneal (i.p) immunization than to epicutaneous (EC) sensitization. A, IL-17A secretion by OVA-stimulated splenocytes. B, IL-17A mRNA expression in OVA-challenged lungs. ∗∗P < .01 and ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2009 124, 761-770.e1DOI: (10.1016/j.jaci.2009.07.040) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 IL-4, but not IL-13, downregulates the systemic IL-17 response and IL-17 expression in lungs of epicutaneously sensitized mice. A, Splenocyte secretion of cytokines in response to OVA stimulation. B, Expression of cytokines in lungs of epicutaneously sensitized mice airway challenged with OVA. ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001. SAL, Saline; NS, not significant. Journal of Allergy and Clinical Immunology 2009 124, 761-770.e1DOI: (10.1016/j.jaci.2009.07.040) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

A, Serum levels of OVA-specific IgE, IgG1, and IgG2a A, Serum levels of OVA-specific IgE, IgG1, and IgG2a. B and C, Eosinophil counts in the peripheral blood (Fig E1B) and IL-5 secretion by OVA-stimulated splenocytes (Fig E1C) in epicutaneously sensitized WT and DKO mice. ND, Not done; SAL, saline. Journal of Allergy and Clinical Immunology 2009 124, 761-770.e1DOI: (10.1016/j.jaci.2009.07.040) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions