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Allergen-dependent oxidant formation requires purinoceptor activation of ADAM 10 and prothrombin  Jie Chen, MSc, MBBS, Jihui Zhang, PhD, Theresa Tachie-Menson,

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Presentation on theme: "Allergen-dependent oxidant formation requires purinoceptor activation of ADAM 10 and prothrombin  Jie Chen, MSc, MBBS, Jihui Zhang, PhD, Theresa Tachie-Menson,"— Presentation transcript:

1 Allergen-dependent oxidant formation requires purinoceptor activation of ADAM 10 and prothrombin 
Jie Chen, MSc, MBBS, Jihui Zhang, PhD, Theresa Tachie-Menson, BSc, Neha Shukla, BSc, David R. Garrod, PhD, Clive Robinson, PhD  Journal of Allergy and Clinical Immunology  Volume 139, Issue 6, Pages e9 (June 2017) DOI: /j.jaci Copyright © 2017 The Authors Terms and Conditions

2 Fig 1 Inhibition by GI X suggests that ADAM 10 is a mediator of intracellular ROS production by (A) HDM allergens (*P < .001 vs vehicle [veh], †P <  vs HDM 1), (B) BzATP (*P < .001 vs veh, ‡P < .001 vs BzATP, **P < .05 vs veh), (C) UTP (*P < .001 vs veh, †P < .001 vs UTP). D-F, ADAM 10 gene silencing also reduces these responses (*P < .001 vs veh, †P < .001 vs HDM 1, BzATP, or UTP with or without control transfection, ‡P < .05 vs BzATP). RFU, Relative fluorescence units. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2017 The Authors Terms and Conditions

3 Fig 2 Recombinant human (rh) ADAM 10 stimulates intracellular ROS formation in airway epithelial cells. A and B, Progress curves and concentration-response relationship for dihydrorhodamine oxidation following vehicle (veh) or rhADAM 10. All concentrations P < .001 with respect to the dashed line. C-E, Inhibition by GI X, AG 1478, or argatroban, respectively, of responses to ADAM 10. BzATP is shown for reference (*P < .001 vs veh, **P < .001 vs ADAM 10, †P < .01 vs veh, ‡P < .001 vs veh). F, Gene-silencing prothrombin (PT) blunts the response to BzATP (*P < .001 vs veh, **P < .05 vs BzATP, †P < .05 vs BzATP stimulation in control transfection, ‡P < .001 vs BzATP stimulation). G, As in Fig 2, F, but stimulation by UTP (*P < .001 vs veh, **P < .001 vs UTP, †P < .05 vs UTP stimulation in control transfection, ‡P < .001 vs UTP). RFU, Relative fluorescence units; rhADAM 10, recombinant human ADAM 10. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2017 The Authors Terms and Conditions

4 Fig E1 Generation of ROS by HDM allergens in airway epithelial cells is dependent on EGFR receptor tyrosine kinase signaling. A, Concentration-dependent inhibition by AG1478 of ROS production by HDM allergens (triangles) or BzATP (circles) (†P < .001 vs control HDM, ‡P < .001 vs control BzATP). B, EGFR-directed siRNA reduces the response to HDM allergens (*P < .001 vs vehicle [veh], †P < .001 vs HDM allergens in cells with or without control [con] transfection). C, Reduction in ROS generation activated by BzATP or UTP in cells treated with EGFR-directed siRNA (*P < .001 vs veh, †P < .001 vs BzATP or UTP with or without con transfection). RFU, Relative fluorescence units. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2017 The Authors Terms and Conditions

5 Fig E2 Effects of metalloprotease inhibitors on ROS generation in human airway epithelial cells stimulated by either HDM allergens or BzATP. A, Marimastat has no effect on baseline ROS production (left panel) but inhibits the response to HDM allergens (right panel) (*P < .001 vs vehicle [veh] or marimastat control, †P < .001 vs cells activated with HDM in the absence of marimastat). B, Concentration-dependent inhibition of HDM responses by TAPI-1 (*P < .001 vs veh, †P < .05, ‡P < .001 vs HDM 1). C, Inhibition of BzATP by TAPI-1 (*P < .001 vs veh, †P < .001 vs BzATP). D, Inhibition of BzATP by marimastat (*P < .001 vs veh or marimastat in unstimulated cells, †P < .001 vs BzATP control). E, Inhibition of the response to HDM allergens by TAPI-2. The control response to HDM allergens is displayed in the left section as a bar graph with mean ± SE shown, and as a dotted line in the concentration-inhibition curve in the right section of this panel (*P < .001 vs veh or TAPI-2 control, †P < .001 vs HDM 1). F, Lack of effect of TAPI-2 on the response to BzATP (*P < .001 vs veh or TAPI-2 control). RFU, Relative fluorescence units. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2017 The Authors Terms and Conditions

6 Fig E3 Effects of metalloprotease inhibitors on ROS generation activated by HDM allergens. A, Modulation of baseline ROS production in airway epithelial cells by WAY (*P < .001, **P < .01 vs vehicle [veh]). B, Inhibition of HDM allergen- or BzATP-dependent ROS production by WAY (*†P < .001 vs veh, **P <  vs HDM, ‡P < .001 vs BzATP). C, Effect of CL on baseline ROS production and lack of action against HDM allergens (*P < .001 vs veh, **P < .05 vs veh, †P < .001 vs veh). D, Effect of ARP 100 on baseline ROS production and failure to inhibit the response to HDM allergens (*P < .001 vs veh, †P = .01 and ‡P < .001 vs HDM allergen). RFU, Relative fluorescence units. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2017 The Authors Terms and Conditions

7 Fig E4 Thrombin dependency of intracellular ROS generation in airway epithelial cells. A, Knockdown of prothrombin (PT) expression by siRNA blunts the response to stimulation by mixed HDM allergens (*P < .001 vs vehicle [veh], †P < .05 vs HDM stimulation in cells with control [con] transfection, ‡P < .001 vs HDM stimulation). B, Concentration-dependent generation of ROS by the snake venom protease, ecarin. Dashed line shows ROS production rate in unstimulated cells. C, CL inhibits ROS generation by exogenous thrombin (*P < .001 vs veh, †P < .001 vs thrombin, ‡P < .05 vs veh). D, GI X inhibits ROS generation by exogenous thrombin (*P < .001 vs veh, †P < .001 vs thrombin). RFU, Relative fluorescence units. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2017 The Authors Terms and Conditions

8 Fig E5 LPS fails to emulate intracellular ROS production by mixed HDM allergens in airway epithelial cells. (*P < .001 vs vehicle [veh], †P < .05 vs veh). LPS content of the mixed HDM preparation was 2.75 endotoxin unit/mL under the conditions of these experiments. RFU, Relative fluorescence units. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2017 The Authors Terms and Conditions

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