Role of IL-17A and neutrophils in fibrosis in experimental hypersensitivity pneumonitis Simon A. Hasan, BSc, Bertus Eksteen, MBChB, FRCP (UK), PhD, Danielle.

Slides:

Advertisements

Similar presentations

Poly (ADP-ribose) polymerase 14 and its enzyme activity regulates TH2 differentiation and allergic airway disease Purvi Mehrotra, PhD, Andrew Hollenbeck,

Advertisements

Innate lymphoid cells contribute to allergic airway disease exacerbation by obesity Laetitia Everaere, PhD, Saliha Ait-Yahia, PhD, Olivier Molendi-Coste,

Fig. 1. Time course of total cells, protein concentration and cytokines in BAL fluid after LPS challenge. The number of total cells, neutrophils and macrophages.

Sejal Saglani, MD, Stephen Lui, PhD, Nicola Ullmann, MD, Gaynor A

Therapeutic reversal of food allergen sensitivity by mature retinoic acid–differentiated dendritic cell induction of LAG3+CD49b−Foxp3− regulatory T cells

Glucagon-like peptide 1 receptor signaling attenuates respiratory syncytial virus– induced type 2 responses and immunopathology Melissa H. Bloodworth,

Thymic stromal lymphopoietin signaling in CD4+ T cells is required for TH2 memory Qun Wang, PhD, Jianguang Du, PhD, Jingjing Zhu, MSc, Xiaowei Yang, MSc,

The Tumor Necrosis Factor Superfamily Molecule LIGHT Promotes Keratinocyte Activity and Skin Fibrosis Rana Herro, Ricardo Da S. Antunes, Amelia R. Aguilera,

The activating protein 1 transcription factor basic leucine zipper transcription factor, ATF- like (BATF), regulates lymphocyte- and mast cell–driven immune.

Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model Sylvie Amu, PhD, Sean P.

The activating protein 1 transcription factor basic leucine zipper transcription factor, ATF- like (BATF), regulates lymphocyte- and mast cell–driven immune.

IL-25 as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis Hyun-Woo Shin, MD, PhD, Dong-Kyu Kim, MD, Min-Hyun Park, MD,

Interferon response factor 3 is essential for house dust mite–induced airway allergy Thomas Marichal, DVM, Denis Bedoret, DVM, PhD, Claire Mesnil, DVM,

Innate IL-13–producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity Jillian L. Barlow, PhD, Agustin Bellosi,

Frank Kirstein, PhD, Natalie E

Maternal house dust mite exposure during pregnancy enhances severity of house dust mite–induced asthma in murine offspring Phoebe K. Richgels, MS, Amnah.

Lack of autophagy induces steroid-resistant airway inflammation

Nazanin Farhadi, MSc, Laura Lambert, BA, Chiara Triulzi, PhD, Peter J

The airway epithelium nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome is activated by urban particulate matter Jeremy A. Hirota,

Pentraxin 3 deletion aggravates allergic inflammation through a TH17-dominant phenotype and enhanced CD4 T-cell survival Jyoti Balhara, MSc, Lianyu Shan,

Compartmentalized chemokine-dependent regulatory T-cell inhibition of allergic pulmonary inflammation Roshi Afshar, PhD, James P. Strassner, BS, Edward.

Role of IL-17A and neutrophils in fibrosis in experimental hypersensitivity pneumonitis Simon A. Hasan, BSc, Bertus Eksteen, MBChB, FRCP (UK), PhD, Danielle.

IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs Chien-Chang Chen, PhD, Takao Kobayashi, PhD, Koji Iijima,

Restoration of T-box–containing protein expressed in T cells protects against allergen- induced asthma Jung Won Park, MD, Hyun Jung Min, MS, Jung Ho Sohn,

Group 2 innate lymphoid cells facilitate sensitization to local, but not systemic, TH2- inducing allergen exposures Matthew J. Gold, BSc, Frann Antignano,

IL-33 induces innate lymphoid cell–mediated airway inflammation by activating mammalian target of rapamycin Robert J. Salmond, PhD, Ananda S. Mirchandani,

Antigen-specific effector CD8 T cells regulate allergic responses via IFN-γ and dendritic cell function Yafang Tang, BSc, Shou Ping Guan, BSc, Benson.

Neonatal rhinovirus induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells Jun Young Hong, MS, J. Kelley.

Allergic airway disease is unaffected by the absence of IL-4Rα–dependent alternatively activated macrophages Natalie E. Nieuwenhuizen, PhD, Frank Kirstein,

Responsiveness to respiratory syncytial virus in neonates is mediated through thymic stromal lymphopoietin and OX40 ligand Junyan Han, PhD, Azzeddine.

Eosinophils contribute to the resolution of lung-allergic responses following repeated allergen challenge Katsuyuki Takeda, MD, PhD, Yoshiki Shiraishi,

Lung dendritic cells induce TH17 cells that produce TH2 cytokines, express GATA-3, and promote airway inflammation Marianne Raymond, PhD, Vu Quang Van,

Signaling through FcRγ-associated receptors on dendritic cells drives IL-33–dependent TH2-type responses Melissa Y. Tjota, BA, Cara L. Hrusch, PhD, Kelly.

Activin A and TGF-β promote TH9 cell–mediated pulmonary allergic pathology Carla P. Jones, PhD, Lisa G. Gregory, PhD, Benjamin Causton, BSc, Gaynor A.

Surfactant protein D inhibits TNF-α production by macrophages and dendritic cells in mice László Hortobágyi, MS, Sonja Kierstein, PhD, Kateryna Krytska,

Ozone exposure induces respiratory barrier biphasic injury and inflammation controlled by IL-33 Chloé Michaudel, PhD, Claire Mackowiak, MSc, Isabelle.

CD4+CD25+ regulatory T cells reverse established allergic airway inflammation and prevent airway remodeling Jennifer Kearley, PhD, Douglas S. Robinson,

Frank Kirstein, PhD, Natalie E

Prominent role of IFN-γ in patients with aspirin-exacerbated respiratory disease John W. Steinke, PhD, Lixia Liu, MD, Phillip Huyett, MD, Julie Negri,

Allergen-induced, eotaxin-rich, proangiogenic bone marrow progenitors: A blood-borne cellular envoy for lung eosinophilia Kewal Asosingh, PhD, Jodi D.

Toll-like receptor 7 gene deficiency and early-life Pneumovirus infection interact to predispose toward the development of asthma-like pathology in mice

Bcl2-like protein 12 plays a critical role in development of airway allergy through inducing aberrant TH2 polarization Zhi-Qiang Liu, MD, PhD, Ying Feng,

Takao Kobayashi, PhD, Koji Iijima, PhD, Alexander L

Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells Elizabeth.

Jethe O. F. Nunes, PhD, Juliana de Souza Apostolico, MSc, David A. G

Janus kinase 1/3 signaling pathways are key initiators of TH2 differentiation and lung allergic responses Shigeru Ashino, PhD, Katsuyuki Takeda, MD,

Ozone exposure induces respiratory barrier biphasic injury and inflammation controlled by IL-33 Chloé Michaudel, PhD, Claire Mackowiak, MSc, Isabelle.

Platelets constitutively express IL-33 protein and modulate eosinophilic airway inflammation Tomohiro Takeda, PhD, Hirotoshi Unno, MD, PhD, Hideaki Morita,

CD4-mediated regulatory T-cell activation inhibits the development of disease in a humanized mouse model of allergic airway disease Helen Martin, MS,

Β2 integrins rather than β1 integrins mediate Alternaria-induced group 2 innate lymphoid cell trafficking to the lung Maya R. Karta, PhD, Peter S. Rosenthal,

Does reduced zona pellucida binding protein 2 (ZPBP2) expression on chromosome 17q21 protect against asthma? Marina Miller, MD, PhD, Christine Vuong,

Role of B cells in TH cell responses in a mouse model of asthma

T-bet inhibits innate lymphoid cell–mediated eosinophilic airway inflammation by suppressing IL-9 production Ayako Matsuki, MD, Hiroaki Takatori, MD,

Sarita Sehra, PhD, Weiguo Yao, PhD, Evelyn T. Nguyen, MS, Nicole L

Lung dendritic cells are stimulated by ultrafine particles and play a key role in particle adjuvant activity Colin de Haar, PhD, Mirjam Kool, BSc, Ine.

T-bet inhibits innate lymphoid cell–mediated eosinophilic airway inflammation by suppressing IL-9 production Ayako Matsuki, MD, Hiroaki Takatori, MD,

Programmed cell death ligand 2 regulates TH9 differentiation and induction of chronic airway hyperreactivity Jerome Kerzerho, PhD, Hadi Maazi, PhD, Anneliese.

Novel allergic asthma model demonstrates ST2-dependent dendritic cell targeting by cypress pollen Lucia Gabriele, BS, Giovanna Schiavoni, BS, Fabrizio.

Poly (ADP-ribose) polymerase 14 and its enzyme activity regulates TH2 differentiation and allergic airway disease Purvi Mehrotra, PhD, Andrew Hollenbeck,

IL-25 as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis Hyun-Woo Shin, MD, PhD, Dong-Kyu Kim, MD, Min-Hyun Park, MD,

Xin-Zi Tang, PhD, James B. Jung, BS, Christopher D.C. Allen, PhD

Monocyte-derived dendritic cell recruitment and allergic TH2 responses after exposure to diesel particles are CCR2 dependent Sharen Provoost, MSc, Tania.

IL-35 production by inducible costimulator (ICOS)–positive regulatory T cells reverses established IL-17–dependent allergic airways disease Gregory S.

Duy Pham, PhD, Sarita Sehra, PhD, Xin Sun, PhD, Mark H. Kaplan, PhD

Rhinovirus infection interferes with induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33 Amit K. Mehta,

No defect in T-cell priming, secondary response, or tolerance induction in response to inhaled antigens in Fms-like tyrosine kinase 3 ligand–deficient.

IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation Kentaro Takahashi, MD, Koichi.

MicroRNA-155 is essential for TH2-mediated allergen-induced eosinophilic inflammation in the lung Carina Malmhäll, BSc, Sahar Alawieh, BSc, You Lu, PhD,

The extra domain A of fibronectin is essential for allergen-induced airway fibrosis and hyperresponsiveness in mice Martin Kohan, MSc, Andres F. Muro,

Transforming growth factor β1 increases fibronectin deposition through integrin receptor α5β1 on human airway smooth muscle Lyn M. Moir, PhD, Janette.

Presentation transcript:

Role of IL-17A and neutrophils in fibrosis in experimental hypersensitivity pneumonitis Simon A. Hasan, BSc, Bertus Eksteen, MBChB, FRCP (UK), PhD, Danielle Reid, MSc, Heather V. Paine, BSc, Abrar Alansary, BSc, Kerri Johannson, MD, FRCPC, Carol Gwozd, MLT, Kimberly-Ann R. Goring, MSc, Tina Vo, BSc, David Proud, PhD, FRCS, Margaret M. Kelly, MBChB, FRCPC, PhD Journal of Allergy and Clinical Immunology Volume 131, Issue 6, Pages 1663-1673.e5 (June 2013) DOI: 10.1016/j.jaci.2013.01.015 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Lung histology after exposure to S rectivirgula antigen. A, Bronchial associated lymphoid tissue (magnification, ×100), lower insert magnification ×400, upper insert goblet cell metaplasia (magnification, ×100; alcian blue/PAS). B, Band of neutrophils (short arrows) and multinucleated giant cells (long arrows) in subpleural region (magnification, ×400; H&E). C, Subpleural fibrosis with infiltrating neutrophils (arrows; H&E). D, CD3+ lymphocytes (arrowheads; diaminobenzidine, brown stain). Area stained with picrosirius red (Fig 1, C) and viewed under brightfield (E) or polarized light (F) to show collagen deposition. G, Myofibroblasts, (α-smooth muscle actin stain, brown) in fibrotic areas close to neutrophils (arrows). H, Tissue neutrophils (arrows) still present after 6 weeks of S rectivirgula antigen (H&E). Exposure was 2 weeks (Fig 1, A and B), 3 weeks (Fig 1, D-G), and 6 weeks (Fig 1, H). All magnification was ×200, unless stated otherwise. Journal of Allergy and Clinical Immunology 2013 131, 1663-1673.e5DOI: (10.1016/j.jaci.2013.01.015) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Exposure to S rectivirgula antigen for 1 to 3, 5, or 6 weeks. BAL fluid and lung tissue were collected 4 days after the last exposure in each group. A, Total inflammatory cells. B, Soluble collagen measured from homogenized right lung (μg/RL). C, KC, IL-17A, and active TGF-β1 (D; pg/mL). *P < .05 compared with weeks 3, 5, and 6. #P < 0.05 compared with weeks 2, 3, 5, and 6. **P < .005 compared with all time points (n = 6 to 8 mice per group). Journal of Allergy and Clinical Immunology 2013 131, 1663-1673.e5DOI: (10.1016/j.jaci.2013.01.015) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Effect of inhibiting active TGF-β on inflammation and fibrosis in EHP. C57BL/6 mice were exposed to 3 weeks of intratracheal PBS or S rectivirgula antigen (SR Ag) and intraperitoneal (IP) anti–TGF-β antibody (Ab) or isotype control. BAL fluid and lung tissue were collected 4 days after last treatment in each group and total inflammatory cells (A), BAL fluid IL-17A (B; pg/mL), and soluble collagen (C; μg/right lung [RL]) were quantified. *P < .05 and **P < .002. Journal of Allergy and Clinical Immunology 2013 131, 1663-1673.e5DOI: (10.1016/j.jaci.2013.01.015) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Effect of IL-17A and neutrophil depletion on total BAL fluid inflammatory cells and fibrosis after chronic exposure to S rectivirgula antigen (SR Ag). Anti–IL-17A (A and B) or Gr-1 (C and D) neutralizing antibody (Ab) were administered to C57BL/6 mice during the last 2 weeks of 3 weeks of exposure to S rectivirgula antigen. A and C, Total BAL fluid inflammatory cells (×103) and (B and D) soluble collagen (μg/right lung [RL]) were measured 4 days after the last exposure to S rectivirgula antigen. Inflammation and fibrosis were compared with saline and appropriate isotype control. *P < .05 compared with saline control (n = 6 to 8 mice per group). IP, Intraperitoneal. Journal of Allergy and Clinical Immunology 2013 131, 1663-1673.e5DOI: (10.1016/j.jaci.2013.01.015) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Loss of IL-17A signaling on structural and/or bone marrow–derived cells during chronic exposure to S rectivirgula antigen. Wild-type (C57BL/6) mice, IL-17RA–deficient (Il17ra−/−) and their bone marrow chimeric mice were exposed to S rectivirgula antigen for 3 weeks. Four days after the last SR exposure, total BAL fluid inflammatory cells (A), BAL fluid KC (B; pg/mL) and soluble collagen (C; μg/right lung [RL]) were measured. *P < .05 compared with Il17ra−/− and strIl17ra−/−, **P < .005 compared with all other groups. #P < .05 compared with Il17ra−/−. Absence of IL17RA on structural cells (strIl17ra−/−) or on bone marrow–derived cells (bmIl17ra−/−); n = 5 to 8 mice per group. Journal of Allergy and Clinical Immunology 2013 131, 1663-1673.e5DOI: (10.1016/j.jaci.2013.01.015) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Neutrophils and monocytes/macrophages are the main IL-17A–secreting cells in EHP. Inflammatory cells were isolated from lung homogenates of mice exposed to 3 weeks of S rectivirgula antigen. IL-17A secreting and nonsecreting cell populations were then isolated. A, FACS-assisted characterization of inflammatory cell populations before and after IL-17A enrichment. ***P < .001. B, Diff-quik and (C) H&E stained cytospins prepared from IL-17A–positive cell fraction show neutrophils (white arrows), macrophages (black arrows) as the main cell types. Representative of 3 independent experiments (n = 2 per experiment). Journal of Allergy and Clinical Immunology 2013 131, 1663-1673.e5DOI: (10.1016/j.jaci.2013.01.015) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Neutrophils and monocytes/macrophages are the main cells that express IL-17A mRNA and protein in EHP in wild-type (WT) and RAG-2–deficient (RAG-2−/−) mice. C57BL/6 or RAG-2–deficient mice were exposed to S rectivirgula antigen for 3 weeks. Leucocytes were isolated and purified, treated with brefeldin A and ionomycin, and stained to assess IL-17A expression by Gr-1–expressing cells A, Representative flow cytometric histograms gated on Gr-1 expression (white peaks, isotype control; gray peaks, IL-17A staining). B, Graphical summary representation of data. C, Gr-1 high and intermediate cells underwent FACS to >99% purity. Representative before and after sort histograms. D, Quantitative reverse-transcription PCR on cell populations that underwent FACS: lymphocyte (CD3), monocyte (Gr-1int), and neutrophil (Gr-1hi). *P < .05 compared with C57BL/6 Gr-1int. **P < .01 compared with C57BL/6 Gr-1int. ***P < .001 compared with C57BL/6 CD3. #P < .001 compared with C57BL/6 Gr-1int. Journal of Allergy and Clinical Immunology 2013 131, 1663-1673.e5DOI: (10.1016/j.jaci.2013.01.015) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Protocol for administration of Saccharopolyspora rectivirgula antigen (SR Ag). S rectivirgula antigen is administered by intratracheal aerosol on 3 consecutive days each week (black arrows) for up to 6 weeks. The mice were sacrificed 4 days after the last aerosol (white arrows), and BAL fluid, blood, and lung tissue were collected. Because inflammation and fibrosis were established after 3 weeks of exposure to S rectivirgula antigen, most outcomes were assessed at this time point. Journal of Allergy and Clinical Immunology 2013 131, 1663-1673.e5DOI: (10.1016/j.jaci.2013.01.015) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 TGF-β activity in the lung in EHP. A, Immunohistochemistry for β6 integrin, a marker of αvβ6 integrin, which is an activator of TGF-β. Strongly positive epithelial cells (arrowheads) are seen in areas of subpleural fibrosis. B, Active TGF-β (pg/mL) in BAL fluid from mice exposed to 3 weeks of intratracheal PBS only or Saccharopolyspora rectivirgula antigen (SR Ag) with intraperitoneal (IP) anti-TGF-β antibody (Ab) or isotype control; n = 5 to 8 mice per group. Journal of Allergy and Clinical Immunology 2013 131, 1663-1673.e5DOI: (10.1016/j.jaci.2013.01.015) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Effect of Gr-1 antibody (Ab) on blood counts after 3 weeks of chronic exposure to Saccharopolyspora rectivirgula antigen (SR Ag) compared with PBS. Gr-1 Ab or isotype control was administered intraperitoneally (IP) twice weekly to wild-type mice exposed to SR Ag or PBS during the last 2 weeks of 3 weeks of pulmonary exposure. A, Blood neutrophils and (B) mononuclear cells (×106/mL) were quantified 4 days after the last exposure to assess efficacy of Gr-1 Ab on systemic neutrophil depletion; n = 6 to 8 mice per group. NS, Not signficant. Journal of Allergy and Clinical Immunology 2013 131, 1663-1673.e5DOI: (10.1016/j.jaci.2013.01.015) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Identification of cell populations that produce IL-17A in EHP with the use of flow cytometry. Inflammatory cells were isolated from whole lung homogenates of wild-type mice after chronic Saccharopolyspora rectivirgula antigen (SR Ag) exposure. Flow cytometry was performed before or after IL-17A capture, using markers for T lymphocytes (CD4/CD3; A), B lymphocytes (CD19/CD3; B), and myeloid-derived cells (C and D). Gr-1high, neutrophils; Gr-1int, CD11c, and MHC II, monocytes/antigen-presenting cells. Journal of Allergy and Clinical Immunology 2013 131, 1663-1673.e5DOI: (10.1016/j.jaci.2013.01.015) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions