Distinct TLR-mediated pathways regulate house dust mite–induced allergic disease in the upper and lower airways Ji-Hwan Ryu, PhD, Jung-Yeon Yoo, BS,

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Distinct TLR-mediated pathways regulate house dust mite–induced allergic disease in the upper and lower airways Ji-Hwan Ryu, PhD, Jung-Yeon Yoo, BS, Min-Ji Kim, BS, Sang-Gyu Hwang, MS, Kwang Chul Ahn, MS, Jae-Chan Ryu, BS, Mi-Kyung Choi, PhD, Jung Hee Joo, PhD, Chang-Hoon Kim, MD, PhD, Sang-Nam Lee, PhD, Won-Jae Lee, PhD, Jaesang Kim, PhD, Dong Min Shin, DDS, PhD, Mi-Na Kweon, PhD, Yun Soo Bae, PhD, Joo-Heon Yoon, MD, PhD Journal of Allergy and Clinical Immunology Volume 131, Issue 2, Pages 549-561 (February 2013) DOI: 10.1016/j.jaci.2012.07.050 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 HDM-derived β-glucans and TLR2 and HDM-derived LPS and TLR4 are responsible for innate immunity in the nasal mucosa and the lung mucosa, respectively. A, Quantification of CCL20 secretion by treatment with HDM extracts (50 μg/mL) for 24 hours in NHNE cells. HDM extracts pretreated with β-glucanase (HDMΔβ-glucan) or polymyxin B (HDMΔLPS). B-I, Mice were intranasally challenged without anesthesia (Fig 1, B, C, F, and G) or with anesthesia (Fig 1, D, E, H, and I) and analyzed 24 hours after the challenge. B and D, CCL20 secretion from NAL fluids (Fig 1, B), or BAL fluid (Fig 1, D) of wild-type (WT) mice. C and E, Percentage of MHCII+CD11c+ DCs in the nasal mucosa (Fig 1, C) or in the lung mucosa (Fig 1, E). F and H, CCL20 secretion from NAL (Fig 1, F) or BAL (Fig 1, H) fluid of WT, TLR2−/−, TLR4−/− mice. G and I, MHCII+CD11c+ DCs in the nasal (Fig 1, G) or the lung (Fig 1, I) mucosa. *P < .05 and **P < .01. All results are shown as means ± SEMs and are representative of 3 independent experiments. Three to 5 mice were used per group. Journal of Allergy and Clinical Immunology 2013 131, 549-561DOI: (10.1016/j.jaci.2012.07.050) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 β-Glucans and LPS within HDM induce TLR2 and TLR4 surface expressions in nasal and bronchial epithelial cells, respectively. The nasal epithelium or bronchial epithelium isolated from the murine airway mucosa was taken and analyzed. A, Basal surface expression level of TLR2 and TLR4 by Western blot analysis. B, TLR2 and TLR4 surface expressions induced by HDM challenge (0, 15, 30, 60 minutes) by fluorescence-activated cell sorting analysis. C, Mean intensity of TLR2 and TLR4 surface expressions from panel B. D, TLR2 and TLR4 surface expressions by HDM challenge (1 hour) in the nasal and bronchial epithelia in the presence (1 hour) or absence of jasplakinolide (1 μmol/L). E, TLR2 and TLR4 surface expressions by challenge with HDM, HDMΔβ-glucan, and HDMΔLPS. *P < .05 and **P < .01. All results are shown as means ± SEMs and are representative of 3 independent experiments. Journal of Allergy and Clinical Immunology 2013 131, 549-561DOI: (10.1016/j.jaci.2012.07.050) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 β-Glucans and LPS within HDM induce TLR2 and TLR4 translocation to lipid rafts in cells of nasal and bronchial epithelia, respectively. A, TLR2 (green) and TLR4 (green) translocation to lipid rafts (caveolin; red) in cells of nasal and bronchial epithelia, respectively, by challenge (1 hour) with HDM in the presence (1 hour) or absence of NAC (10 mmol/L), or with HDMΔβ-glucan, HDMΔLPS, respectively (50 μg/mL). B, CCL20 secretion and MHCII+CD11c+ DCs in the nasal mucosa by HDM challenge (24 hours) in the presence or absence of methyl-beta-cyclodextrin (MβCD) (1 mmol/L). C, CCL20 secretion and MHCII+CD11c+ DCs in the lung mucosa by HDM challenge in the presence or absence of MβCD (1 mmol/L). *P < .05 and **P < .01. All results are shown as means ± SEMs and are representative of 3 independent experiments. Three to 5 mice were used per group. Journal of Allergy and Clinical Immunology 2013 131, 549-561DOI: (10.1016/j.jaci.2012.07.050) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 HDM-induced ROS is responsible for innate immunity in both the nasal and the bronchial epithelium. A, TLR2 and TLR4 surface expressions by HDM challenge in the nasal and bronchial epithelia in the presence or absence of NAC (10 mmol/L). B, CCL20 secretion and MHCII+CD11c+ DCs in the nasal mucosa by HDM challenge in the presence or absence of NAC. C, CCL20 secretion and MHCII+CD11c+ DCs in the lung mucosa by HDM challenge in the presence or absence of NAC. D and E, ROS generation was analyzed in primary nasal and bronchial epithelial cells cultured from the wild-type (WT) murine airway epithelium (Fig 4, D), or WT, TLR2−/−, and TLR4−/− airway epithelia (Fig 4, E). *P < .05 and **P < .01. All results are shown as means ± SEMs and are representative of 3 independent experiments. Three to 5 mice were used per group. Journal of Allergy and Clinical Immunology 2013 131, 549-561DOI: (10.1016/j.jaci.2012.07.050) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 DUOX2 is responsible for HDM-induced innate immunity in both nasal and bronchial epithelium. A, TLR2 and TLR4 surface expressions by HDM in the nasal and bronchial epithelia isolated from the DUOX2+/+ or DUOX2thyd/thyd airway mucosa. B, TLR2 (green) and TLR4 (green) translocation to lipid rafts (caveolin; red) in cells of nasal and bronchial epithelia, respectively, by HDM challenge. C and D, CCL20 secretion and MHCII+CD11c+ DCs by HDM challenge in the nasal mucosa (Fig 5, C) and lung mucosa (Fig 5, D) of DUOX2+/+ or DUOX2thyd/thyd mice. *P < .05 and **P < .01. All results are shown as means ± SEMs and are representative of 3 independent experiments. Three to 5 mice were used per group. Journal of Allergy and Clinical Immunology 2013 131, 549-561DOI: (10.1016/j.jaci.2012.07.050) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 β-Glucans and LPS within HDM are responsible for HDM-induced AR and AA, respectively. A-C, Wild-type (WT) mice were sensitized with HDM extract and consequent provocation by intranasal challenging with PBS (HDM/PBS), HDM extracts (HDM/HDM), HDMΔβ-glucan (HDM/HDMΔβ-glucan), and HDMΔLPS (HDM/HDMΔLPS), without anesthesia. A, Frequencies of nose scratching. B, CCR3+CD3− eosinophils in the nasal mucosa. C, Cytokine production in cervical lymph node cells restimulated ex vivo for 4 days with PBS, HDM, HDMΔβ-glucan, and HDMΔLPS. D-F, WT mice were sensitized as in panels A-C and consequent provocation by intranasal challenging under anesthesia. D, Periodic acid-Schiff staining of lung tissue. E, CCR3+CD3− eosinophils from the BAL fluid. F. Cytokine production in the mediastinal lymph node cells restimulated as in panel C. *P < .05 and **P < .01. All results shown are means ± SEMs and are representative of 4 independent experiments. Three to 5 mice were used per group. Journal of Allergy and Clinical Immunology 2013 131, 549-561DOI: (10.1016/j.jaci.2012.07.050) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 TLR2 and TLR4 are required for HDM-induced AR and AA, respectively, and DUOX2 is responsible for both HDM-induced AR and AA. A-F, Wild-type (WT), TLR2−/−, TLR4−/−, DUOX2+/+, and DUOX2thyd/thyd mice were used in HDM-induced AR (Fig 7, A-C) or AA (Fig 7, D-F) as in Fig 6. A, Nose scratching. B, CCR3+CD3− eosinophils in the nasal mucosa. C, Cytokine production in restimulated cervical lymph node cells. D, Periodic acid–Schiff staining of lung tissue. E, CCR3+CD3− eosinophils from the BAL fluid. F, Cytokine production in restimulated mediastinal lymph node cells. *P < .05 and **P < .01. All results are shown as means ± SEMs and are representative of 4 independent experiments. Three to 5 mice were used per group. Journal of Allergy and Clinical Immunology 2013 131, 549-561DOI: (10.1016/j.jaci.2012.07.050) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2013 131, 549-561DOI: (10.1016/j.jaci.2012.07.050) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2013 131, 549-561DOI: (10.1016/j.jaci.2012.07.050) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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Fig E4 Journal of Allergy and Clinical Immunology 2013 131, 549-561DOI: (10.1016/j.jaci.2012.07.050) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2013 131, 549-561DOI: (10.1016/j.jaci.2012.07.050) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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Fig E7 Journal of Allergy and Clinical Immunology 2013 131, 549-561DOI: (10.1016/j.jaci.2012.07.050) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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Fig E13 Journal of Allergy and Clinical Immunology 2013 131, 549-561DOI: (10.1016/j.jaci.2012.07.050) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E14 Journal of Allergy and Clinical Immunology 2013 131, 549-561DOI: (10.1016/j.jaci.2012.07.050) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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Fig E16 Journal of Allergy and Clinical Immunology 2013 131, 549-561DOI: (10.1016/j.jaci.2012.07.050) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions