Desiccating stress worsens alkali burn injury by magnifying caspase-8-induced imbalance of NLRP3 and NLRP6 Xia Hua, MD, PhD, Xiaoyong Yuan, MD, PhD,

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Presentation transcript:

Desiccating stress worsens alkali burn injury by magnifying caspase-8-induced imbalance of NLRP3 and NLRP6 Xia Hua, MD, PhD, Xiaoyong Yuan, MD, PhD, Yonghao Li, MD, PhD, Hui Chen, MD, Jin Yuan, MD, PhD, Silvia Tanumiharjo, MD, Fang Bian, MD, PhD, Lishi Su, BS, Yanhua Hong, BS, Yizhi Liu, MD, PhD, Wei Chi, MD, PhD Journal of Allergy and Clinical Immunology Volume 140, Issue 4, Pages 1172-1176.e3 (October 2017) DOI: 10.1016/j.jaci.2017.04.018 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 AB-induced imbalance of NLRP3/NLRP6 magnified by DS and NLRP3 promoted and NLRP6 protected against the ocular surface disorder induced by AB and DS injury. A, B, D-F, NLRP3, ASC, and NLRP6 gene and protein expression treated with AB combined with or without DS and with or without NLRP3 inhibitor or NLRP6 siRNA. Graph of the relative densities of NLRP3, NLRP6, and ASC normalized to β-actin for WB results. C, NLRP3 promoted caspase-1 activity. G, Rate of corneal perforation. H and I, Representative images of corneas and corneal wounds closure. J and K, NLRP3 and NLRP6 regulated the processing of IL-1β and IL-18. P3 inh, NLRP3 inhibitor, glybenclamide; P6 si, NLRP6 siRNA; UT, untreated; WB, Western blot. Representative images are shown. Data are presented as mean ± SD. Experiments were repeated 3 times with similar results. *P < .05. **P < .001. Journal of Allergy and Clinical Immunology 2017 140, 1172-1176.e3DOI: (10.1016/j.jaci.2017.04.018) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Caspase-8 activation regulated the imbalance of NLRP3 and NLRP6 in AB-induced and DS-worsened ocular surface injury. A, Caspase-8 activity treated with AB combined with or without DS and with or without caspase-8 inhibitor, NLRP3 inhibitor, or NLRP6 siRNA. B and C, Representative pictures of cornea and corneal wounds closure. D, Rate of corneal perforation. E-G, Caspase-8 promoted the processing of IL-1β and IL-18. Graph of the densities of pro–IL-1β, IL-1β, pro–IL-18, and IL-18 normalized to β-actin. H-K, Caspase-8 regulated NLRP3, NLRP6, and ASC expression. Graph of the densities of NLRP3, NLRP6, and ASC normalized to β-actin. L, Caspase-8 drove caspase-1 activity. C8 inh, Caspase-8 inhibitor Z-IETD-fmk; UT, untreated. Representative images are shown. Data are presented as mean ± SD. The experiments were repeated 3 times with similar results. *P < .05. **P < .001. Journal of Allergy and Clinical Immunology 2017 140, 1172-1176.e3DOI: (10.1016/j.jaci.2017.04.018) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 The effects of caspase-8 inhibitor Z-IETD-fmk, NLRP3 inhibitor glybenclamide, and NLRP6 siRNA at different doses. A, Caspase-8 activity was suppressed by caspase-8 inhibitor Z-IETD-fmk at different doses (20, 40, and 60 μM). Caspase-8 activation was largely inhibited at doses of 40 and 60 μM and a dose of 40 μM was therefore used for subsequent experiments. B, Different doses of NLRP3 inhibitor, glybenclamide (30, 60, and 120 μM), were used to determine the effective dose. A dose of 120 μM glybenclamide primarily inhibits the expression of NLRP3 as evaluated by WB. C, Different doses of NLRP6 siRNA (10, 50, and 100 nM) were used and the doses of 50 and 100 nM largely knocked down NLRP6, compared with control siRNA. A dose of 50 nM was chosen for subsequent experiments. C8 inh, Caspase-8 inhibitor Z-IETD-fmk; UT, untreated; WB, Western blot. The experiment was repeated 3 times with similar results. Representative images are shown. Data are presented as mean ± SD of the fold increase compared with controls. *P < .05. **P < .001. Journal of Allergy and Clinical Immunology 2017 140, 1172-1176.e3DOI: (10.1016/j.jaci.2017.04.018) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Inhibition of caspase-8 by caspase-8 inhibitor Z-IETD-fmk. A, Representative WB images showed that caspase-8 protein levels were significantly elevated in the AB group compared with the untreated group, were magnified by DS combined AB, and were largely suppressed after caspase-8 inhibition. B, Graph of the densities of caspase-8 normalized to β-actin. C8 inh, Caspase-8 inhibitor Z-IETD-fmk; UT, untreated. The experiment was repeated 3 times with similar results. Representative images are shown. Data are presented as mean ± SD of the fold increase compared with controls. *P < .05. **P < .001. Journal of Allergy and Clinical Immunology 2017 140, 1172-1176.e3DOI: (10.1016/j.jaci.2017.04.018) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions