Innate mechanism of pollen- and cat dander–induced oxidative stress and DNA damage in the airways Koa Hosoki, MD, PhD, David Redding, MD, Toshiko Itazawa,

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Innate mechanism of pollen- and cat dander–induced oxidative stress and DNA damage in the airways Koa Hosoki, MD, PhD, David Redding, MD, Toshiko Itazawa, MD, PhD, Anirban Chakraborty, PhD, Nisha Tapryal, PhD, Sun Qian, PhD, Huibin Qi, PhD, Leopoldo Aguilera-Aguirre, PhD, Allan R. Brasier, PhD, Veeranki Sreenivas Phani, PhD, Tapas K. Hazra, PhD, Istvan Boldogh, PhD, Sanjiv Sur, MD Journal of Allergy and Clinical Immunology Volume 140, Issue 5, Pages 1436-1439.e5 (November 2017) DOI: 10.1016/j.jaci.2017.04.044 Copyright © 2017 Terms and Conditions

Fig 1 TLR4-dependent intracellular ROS generation. A, Many allergenic extracts induce greater ROS generation in TLR4Hi cells compared with TLR4Null cells (n = 6-11 per group). B, Some allergenic extracts and LPS do not induce TLR4-dependent ROS generation (n = 6-11 per group). C, RWPE and CDE induce a greater increase in GSSG in supernatants from TLR4Hi than TLR4Null cells (n = 5 per group). H2DCF-DA, 2′,7′-Dichlorodihydrofluoresceine diacetate. *P < .05, **P < .01, ***P < .001, and ****P < .0001. NS, Not significant. Journal of Allergy and Clinical Immunology 2017 140, 1436-1439.e5DOI: (10.1016/j.jaci.2017.04.044) Copyright © 2017 Terms and Conditions

Fig 2 TLR4-dependent oxidative stress and DNA damage induced by allergenic extracts. A and B, Single challenge with RWPE (Fig 2, A) or CDE (Fig 2, B) induces greater levels of GSSG in BALF of WT than Tlr4 knockout mice. In the WT or TLR4 antioxidant group, N-acetyl cysteine and ascorbic acid was administered 1 hour before RWPE challenge (n = 5-8 per group). C, RWPE induces greater reductions in intracellular antioxidant glutathione (iGSH) levels in TLR4Hi than in TLR4Null cells (n = 5 per group). D, RWPE induces greater mitochondrial ROS generation in TLR4Hi than TLR4Null cells (n = 3-4 per group). E, RWPE induces greater comet tail moments in TLR4Hi than TLR4Null cells (n = 50 per group). F, RWPE induces greater damage in the lung genomic DNA from WT compared with Tlr4 knockout mice (n = 5-6 per group). *P < .05, **P < .01, ***P < .001, and ****P < .0001. NS, Not significant. Journal of Allergy and Clinical Immunology 2017 140, 1436-1439.e5DOI: (10.1016/j.jaci.2017.04.044) Copyright © 2017 Terms and Conditions

Fig E1 Coimmunoprecipitation/western blot analysis. HEK 293 cells stably overexpressing HA-tagged TLR4 but not MD2 (TLR4HA) were transfected with plasmid encoding MD2 to generate TLR4-MD2 expressing cells (TLR4HA-MD2).E6 Stimulation of TLR4Hi-MD2 cells with RWPE induced rapid association of TRAF6 with TLR4 in 10 and 30 minutes. IP, Immunoprecipitation; WB, Western blotting. Journal of Allergy and Clinical Immunology 2017 140, 1436-1439.e5DOI: (10.1016/j.jaci.2017.04.044) Copyright © 2017 Terms and Conditions

Fig E2 RWPE challenge rapidly increases oxidative DNA damage in the noses of allergic human subjects. Intranasal RWPE challenge in human subjects is shown. Patients with allergic rhinitis and positive skin prick test responses to RWPE were challenged with saline on one day and RWPE on another. A, RWPE challenge increased nasal symptom scores for congestion, drainage, and sneezing recorded on subjective scale scores of 0 to 3, yielding a combined total symptom score for all 3 symptoms of a maximum of 9. B, RWPE challenge increased levels of 8-OHdG in nasal fluids 30 minutes after challenge. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2017 140, 1436-1439.e5DOI: (10.1016/j.jaci.2017.04.044) Copyright © 2017 Terms and Conditions