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NADPH oxidase-regulator of host defense and inflammation (CGD) PowerPoint Presentation

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  • Slide 1 - NADPH oxidase: regulator of host defense and inflammation Brahm Segal, MD Roswell Park Cancer Institute
  • Slide 2 - Innate Immunity against Aspergillus Segal, BH, N Engl J Med. 2009 Apr 30;360(18):1870-84
  • Slide 3 - HEME HOCI H2O2 SOD NADP+ + H+ NADPH MPO O2 O2– p22phox gp91phox e– FAD e– rac GTP HEME HEME p22phox gp91phox FAD HEME rac p7phox RhoGDI GDP p67phox p47phox p40phox p67phox p47phox p40phox NADPH oxidase Activation Cytoplasm Activation of primary granular proteases
  • Slide 4 - Infectious complications in CGD patients
  • Slide 5 - Inflammatory complications of CGD
  • Slide 6 - Invasive aspergillosis in a mouse model of chronic granulomatous disease
  • Slide 7 - HEME HOCI H2O2 SOD NADP+ + H+ NADPH MPO O2 O2– p22phox gp91phox e– FAD e– rac GTP HEME HEME p22phox gp91phox FAD HEME rac p7phox RhoGDI GDP p67phox p47phox p40phox p67phox p47phox p40phox NADPH oxidase Activation Cytoplasm Activation of primary granular proteases
  • Slide 8 - Reeves et al. Killing activity of neutrophils is mediated through activation of proteases by K+ flux Nature 2002 Tkalcevik et al. Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G. Immunity, 2000
  • Slide 9 - Hypothesis Double KO Neutrophil elastase (NE) and cathepsin G (CG) mice will be as susceptible to aspergillosis as NADPH oxidase-deficient mice
  • Slide 10 - Survival after Aspergillus challenge (1.25 x 104 CFU/mouse)
  • Slide 11 - Survival after Aspergillus challenge (1.25 x 107 CFU/mouse)
  • Slide 12 - WT and NE-/- x CG-/- have similar lung fungal burden after Aspergillus challenge (day 3, 1.25 x 107 CFU/mouse)
  • Slide 13 - Invasive aspergillosis in a mouse model of chronic granulomatous disease 1.25 x 104 CFU/mouse
  • Slide 14 - Lung histology in WT mouse WT mouse, day 3, 1.25 x 107 CFU/mouse
  • Slide 15 - Lung histology in NE-/- x CG-/-mouse NE-/- x CG-/- mouse, day 3, 1.25 x 107 CFU/mouse
  • Slide 16 - Conclusions NADPH oxidase is critical -- but NE and CG are dispensable -- in host defense against pulmonary aspergillosis Potentially, NADPH oxidase-mediated activation of other antimicrobial proteins compensate for loss of NE and CG Future studies: We will evaluate the requirement for NADPH oxidase vs. NE and CG in a bacterial challenge model (Burkholderia cepacia)
  • Slide 17 - Wildtype X-CGD
  • Slide 18 - Copyright ©2006 American Society for Clinical Investigation Iwakura, Y. et al. J. Clin. Invest. 2006;116:1218-1222 IL-23 promotes the development of an IL-17-producing CD4+ helper T cell subset
  • Slide 19 - Tryptophan metabolism
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  • Slide 21 - NADPH oxidase and inflammation Aim: evaluate the role of NADPH oxidase in regulating inflammatory responses following challenge with sterile intratracheal zymosan Rationale for zymosan Pro-inflammatory fungal cell wall constituent used widely in models of inflammation Avoids confounding effect of impaired host defense against aspergillosis in CGD mice Ligand of Dectin-1, TLR-2, and CR3 Activates NADPH oxidase via Dectin-1-dependent signalling
  • Slide 22 - ppt slide no 22 content not found
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  • Slide 25 - BALF IL-17 concentration after i.t. zymosan *
  • Slide 26 - Lung lymphocytes from CGD mice administered zymosan are enriched in IL-17+ cells
  • Slide 27 - Lung lymphocytes from CGD mice administered zymosan have diminished Tregs versus wildtypes
  • Slide 28 - Unstimulated PMA-stimulated Neutrophil NADPH oxidase activity after bone marrow transplantation
  • Slide 29 - NADPH oxidase in hematopoietic cells govern the inflammatory phenotype
  • Slide 30 - Dectin-1-/- mice and aspergillosis Dectin-1-/- neutrophils diminished NADPH oxidase activation after exposure to A. fumigatus Diminished antifungal activity in vitro In vivo, Dectin-1-/- mice have impaired host defense following A. fumigatus challenge Impaired neutrophil recruitment to the lungs and production of IL-17 and other pro-inflammatory cytokines and chemokines Werner et al. J Immunol, 2009
  • Slide 31 - Fungal b-glucans Dectin-1 NADPH oxidase activation Activation of neutrophil proteases Tregs IDO activation Innate Adaptive Tn-17 Th-2
  • Slide 32 - NADPH oxidase as a regulator of transcription factors
  • Slide 33 - Lung NF-kB activation after i.t. zymosan * * * *, p<0.01
  • Slide 34 - NF-kB activation in immortalized BM-derived Macrophages after zymosan stimulation
  • Slide 35 - CGD mice develop increased inflammation after i.t. LPS Wildtype CGD
  • Slide 36 - Lung NF-kB activation after i.t. LPS
  • Slide 37 - NF-kB activation in immortalized BM-derived Macrophages after LPS stimulation
  • Slide 38 - IKK complex NF-kB NF-kB binding motif HEME FAD ROIs Pro-inflammatory cytokines and chemokines ?
  • Slide 39 - Nrf-2 Transcriptional factor: binds to antioxidant response element (ARE) Nrf2-regulated genes encode almost all of the relevant antioxidant proteins HO-1, g-glutamyl cysteine synthase, and several members of the GST family Under basal conditions, Nrf2 undergoes rapid ubiquitination by CUL3 (a ubiquitin ligase), with subsequent proteasome-dependent degradation Keap1 is an oxidative stress sensor that functions as an adaptor for CUL3 Oxidation or adduction of critical Keap1 cysteine residues induces a conformational change in Keap1 that inhibits its ability to bind to CUL3, thereby abrogating Nrf2 ubiquitination
  • Slide 40 - Phenotype of Nrf2-/- mice Increased inflammation in multiple experimental models (e.g., colitis, diesel particles, LPS-induced shock, smoking-induced lung disease) Increased sensitivity to multiple experimental tumor models (e.g., chemically-induced gastric and bladder cancer)
  • Slide 41 - NADPH oxidase and Nrf2 Is NADPH oxidase required for Nrf2 activation during lung inflammation? Can excessive inflammation in CGD mice be restrained by pharmacological Nrf2 activation?
  • Slide 42 - NQO1 b-actin A B C D Nrf-2 activation is impaired in CGD macrophages
  • Slide 43 - C D E F * * * * B) Zymosan+ CDDO-Im A) Zymosan+ vehicle
  • Slide 44 - Effect of CDDO-Im started 2 days after i.t. zymosan
  • Slide 45 - Nrf2-/- develop self-limited increased zymosan-induced lung inflammation Day 3 D
  • Slide 46 - Normals (n=8), CGD patients (n=5), *=p<0.05 compared to WT PBMCs PBMCs from CGD patients have increased zymosan-induced NF-kB activation vs. WT donor PBMCs
  • Slide 47 - Normals (n=8), CGD patients (n=5), * p<0.05 comparing WT with CGD PBMCs PBMCs from CGD patients have defective Nrf2 activation
  • Slide 48 - Summary NADPH oxidase downregulates LPS- and zymosan-stimulated inflammation and NF-kB activation. CDDO-Im, an Nrf2 activator, significantly reduced zymosan-induced inflammation and BALF TNF-a and IL-17 levels in CGD mice CGD and Nrf2-/- mice have distinct inflammatory phenotypes Nrf2 is likely to be an important, but not the sole, mechanisms by which NADPH oxidase restrains inflammation Consistent with mouse data, studies of PBMCs from X-linked CGD patients demonstrate NADPH oxidase as a Nrf2 activator, while restraining NF-kB activation.
  • Slide 49 - Nrf2 Keap1 Antioxidant and anti-inflammatory proteins IKK complex NF-kB NF-kB binding ARE motif sequence HEME FAD Cys ? ROIs Pro-inflammatory cytokines and chemokines Tn-17 Treg
  • Slide 50 - Luigina Romani Paolo Puccetti Università degli Studi di Perugia Steve Holland Don Vinh Thomas Walsh Brahm Segal Robert Swamidoss Melissa Grimm Carly Dennis Jen Bushey Joy Feminella Tim Blackwell Mike Freeman Wei Han Funding: CGD Research Trust, NIH

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