Regulated in development and DNA damage responses 1 (REDD1) links stress with IL- 1β–mediated familial Mediterranean fever attack through autophagy-driven.

Slides:

Advertisements

Similar presentations

Maria B. Sukkar, PhD, Shaoping Xie, PhD, Nadia M

Advertisements

Asthmatic airway epithelial cells differentially regulate fibroblast expression of extracellular matrix components Stephen R. Reeves, MD, PhD, Tessa.

Multiple-checkpoint inhibition of thymic stromal lymphopoietin–induced TH2 response by TH17-related cytokines Sofia I. Bogiatzi, BSc, Maude Guillot-Delost,

MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers Thomas X. Lu,

Inhaled long-acting β2 agonists enhance glucocorticoid receptor nuclear translocation and efficacy in sputum macrophages in COPD Rubaiyat Haque, MBBS,

Flow cytometry imaging identifies rare TH2 cells expressing thymic stromal lymphopoietin receptor in a “proallergic” milieu Amanda J. Reefer, MS, Kathryn.

Regulatory T cells as a biomarker for response to adalimumab in rheumatoid arthritis Dao X. Nguyen, BSc, Alice Cotton, RN, BSc, Laura Attipoe, MBBS, Coziana.

Human circulating group 2 innate lymphoid cells can express CD154 and promote IgE production Laura Maggi, PhD, Gianni Montaini, BSc, Alessio Mazzoni,

Asthma inflammatory phenotypes show differential microRNA expression in sputum Tania Maes, PhD, Francisco Avila Cobos, MSc, Florence Schleich, MD, PhD,

Thymic stromal lymphopoietin downregulates filaggrin expression by signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated.

Proviral integration site for Moloney murine leukemia virus 1, but not phosphatidylinositol-3 kinase, is essential in the antiapoptotic signaling cascade.

CD4+ T cells in patients with chronic inflammatory rheumatic disorders show distinct levels of exhaustion Theresa Frenz, PhD, Elena Grabski, PhD, Daniela.

IL-10 disrupts the Brd4-docking sites to inhibit LPS-induced CXCL8 and TNF-α expression in monocytes: Implications for chronic obstructive pulmonary disease

Defective nuclear entry of hydrolases prevents neutrophil extracellular trap formation in patients with chronic granulomatous disease Susana Romao, PhD,

MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers Thomas X. Lu,

Bruton tyrosine kinase mediates TLR9-dependent human dendritic cell activation Vassilios Lougaris, MD, Manuela Baronio, PhD, Massimiliano Vitali, PhD,

IL-32 is expressed by human primary keratinocytes and modulates keratinocyte apoptosis in atopic dermatitis Norbert Meyer, MD, Maya Zimmermann, PhD,

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

Reduction of CRKL expression in patients with partial DiGeorge syndrome is associated with impairment of T-cell functions Mauro Giacomelli, PhD, Rajesh.

Differential control of TH1 versus TH2 cell responses by the combination of low-dose steroids with β2-adrenergic agonists Elena Goleva, PhD, Annegret.

Is 9 more than 2 also in allergic airway inflammation?

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.

Human mast cells arise from a common circulating progenitor

Dawn C. Newcomb, PhD, Madison G

Cysteinyl leukotriene E4 activates human group 2 innate lymphoid cells and enhances the effect of prostaglandin D2 and epithelial cytokines Maryam Salimi,

Staphylococcus aureus enhances the tight junction barrier integrity in healthy nasal tissue, but not in nasal polyps Can Altunbulakli, MSc, Rita Costa,

A critical role for IL-18 in transformation and maturation of naive eosinophils to pathogenic eosinophils Sathisha Upparahalli Venkateshaiah, PhD, Akanksha.

Bullous pemphigoid outcome is associated with CXCL10-induced matrix metalloproteinase 9 secretion from monocytes and neutrophils but not lymphocytes

Programmed cell death ligand 1 alleviates psoriatic inflammation by suppressing IL-17A production from programmed cell death 1–high T cells Jong Hoon.

Increased neutrophilia in nasal polyps reduces the response to oral corticosteroid therapy Weiping Wen, PhD, Wenlong Liu, MD, Luo Zhang, PhD, Jing Bai,

Human mast cell degranulation and preformed TNF secretion require mitochondrial translocation to exocytosis sites: Relevance to atopic dermatitis Bodi.

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,

FcɛRI cross-linking and IL-3 protect human basophils from intrinsic apoptotic stress Lionel Rohner, MSc, Ramona Reinhart, PhD, Björn Hagmann, PhD, Andrea.

Human mast cells drive memory CD4+ T cells toward an inflammatory IL-22+ phenotype Nicolas Gaudenzio, PhD, Camille Laurent, MD, Salvatore Valitutti,

Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages Elena Goleva, PhD, Pia J. Hauk, MD, Clifton.

Multiple-checkpoint inhibition of thymic stromal lymphopoietin–induced TH2 response by TH17-related cytokines Sofia I. Bogiatzi, BSc, Maude Guillot-Delost,

Potentiation of IL-19 expression in airway epithelia by IL-17A and IL-4/IL-13: Important implications in asthma Fei Huang, PhD, Shinichiro Wachi, PhD,

Cigarette smoke combined with Toll-like receptor 3 signaling triggers exaggerated epithelial regulated upon activation, normal T-cell expressed and secreted/CCL5.

Allison K. Martin, BS, Douglas G. Mack, PhD, Michael T

Inhibition of angiogenesis by IL-32: Possible role in asthma

Activin A is an acute allergen-responsive cytokine and provides a link to TGF-β– mediated airway remodeling in asthma Christian Karagiannidis, MD, Gabriele.

Peanut-induced intestinal allergy is mediated through a mast cell–IgE–FcεRI–IL-13 pathway Meiqin Wang, MD, PhD, Katsuyuki Takeda, MD, PhD, Yoshiki Shiraishi,

Thymic stromal lymphopoietin–activated invariant natural killer T cells trigger an innate allergic immune response in atopic dermatitis Wen Hao Wu, PhD,

Cytosolic phospholipase A2 group IVA is overexpressed in patients with persistent asthma and regulated by the promoter microsatellites Milena Sokolowska,

Time for a paradigm shift in asthma treatment: From relieving bronchospasm to controlling systemic inflammation Leif Bjermer, MD Journal of Allergy.

Mammalian target of rapamycin inhibition counterbalances the inflammatory status of immune cells in patients with chronic granulomatous disease Aurélie.

Statins enhance the anti-inflammatory effects of inhaled corticosteroids in asthmatic patients through increased induction of indoleamine 2, 3-dioxygenase

Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 (STAT1) Kornvalee Meesilpavikkai,

IκB kinase–driven nuclear factor-κB activation in patients with asthma and chronic obstructive pulmonary disease Rosalia Gagliardo, PhD, Pascal Chanez,

Individual IL-3 priming is crucial for consistent in vitro activation of donor basophils in patients with chronic urticaria Thomas Gentinetta, MSc, Tatjana.

Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease Javier Milara, PhD, PharmD,

Autophagy: Nobel Prize 2016 and allergy and asthma research

IL-17E upregulates the expression of proinflammatory cytokines in lung fibroblasts Séverine Létuvé, PhD, Stéphane Lajoie-Kadoch, MSc, Séverine Audusseau,

TGF-β1–induced phospholamban expression alters esophageal smooth muscle cell contraction in patients with eosinophilic esophagitis Lisa Y. Beppu, BS,

Splicing defect of CD33 and inflammatory syndrome associated with occult bacterial infection Maria L. Balmer, MD, PhD, Beat Trüeb, PhD, Lei Zhuang, PhD,

Association between specific timothy grass antigens and changes in TH1- and TH2-cell responses following specific immunotherapy Véronique Schulten, PhD,

Sara Paveglio, PhD, MS, Erin Bennett, MS, Kelly L. Hawley, PhD, Adam P

Correlation between CCL26 production by human bronchial epithelial cells and airway eosinophils: Involvement in patients with severe eosinophilic asthma

The steroidogenic enzyme Cyp11a1 is essential for development of peanut-induced intestinal anaphylaxis Meiqin Wang, MD, PhD, Julita Ramirez, DVM, PhD,

Allergy to human seminal fluid: Cross-reactivity with dog dander

CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4 Kandace Bonner,

Biju Thomas, MD, Robert Anthony Hirst, PhD, Mina H

Eosinophil and neutrophil extracellular DNA traps in human allergic asthmatic airways Ryszard Dworski, MD, PhD, Hans-Uwe Simon, MD, PhD, Aimee Hoskins,

Role of TGF-β in anti-rhinovirus immune responses in asthmatic patients Carina Bielor, Nina Sopel, PhD, Anja Maier, MSc, Ashley Blau, Himanshu Sharma,

Cigarette smoke exposure is associated with vitamin D3 deficiencies in patients with chronic rhinosinusitis Jennifer K. Mulligan, PhD, Whitney Nagel,

Neuropeptide signaling through neurokinin-1 and neurokinin-2 receptors augments antigen presentation by human dendritic cells Junya Ohtake, PhD, Shun.

Nuclear factor (erythroid-derived 2)-like-2 pathway modulates substance P–induced human mast cell activation and degranulation in the hair follicle Laura.

Statins enhance the anti-inflammatory effects of inhaled corticosteroids in asthmatic patients through increased induction of indoleamine 2, 3-dioxygenase

CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4 Kandace Bonner,

Presentation transcript:

Regulated in development and DNA damage responses 1 (REDD1) links stress with IL- 1β–mediated familial Mediterranean fever attack through autophagy-driven neutrophil extracellular traps Panagiotis Skendros, MD, PhD, Akrivi Chrysanthopoulou, PhD, François Rousset, MSc, Konstantinos Kambas, PhD, Athanasios Arampatzioglou, MSc, Alexandros Mitsios, BSc, Veronique Bocly, BSc, Theocharis Konstantinidis, MD, Philippe Pellet, BSc, Iliana Angelidou, MSc, Eirini Apostolidou, MD, Dimitrios Ritis, MSc, Victoria Tsironidou, BSc, Sotiris Galtsidis, PhD, Charalampos Papagoras, MD, PhD, Dimitrios Stakos, MD, PhD, Georgios Kouklakis, MD, PhD, Vasiliki Dalla, MD, PhD, Maria Koffa, PhD, Ioannis Mitroulis, MD, PhD, Ioannis Theodorou, MD, PhD, Konstantinos Ritis, MD, PhD Journal of Allergy and Clinical Immunology Volume 140, Issue 5, Pages 1378-1387.e13 (November 2017) DOI: 10.1016/j.jaci.2017.02.021 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Journal of Allergy and Clinical Immunology 2017 140, 1378-1387 Journal of Allergy and Clinical Immunology 2017 140, 1378-1387.e13DOI: (10.1016/j.jaci.2017.02.021) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 REDD1 overexpression during FMF attacks. A and B, Transcriptomic (Fig 1, A) and heat map (Fig 1, B; false discovery rate < 0.05) analysis between neutrophils from patients with FMF attacks and neutrophils from patients in remission (n = 3). In Fig 1, A, β-tubulin (TUBB) is displayed as a negative control. C and D, REDD1 mRNA levels (Fig 1, C; n = 6) and REDD1 or p62/SQSTM1 immunoblotting (Fig 1, D; n = 4) in neutrophils from patients with FMF attacks in comparison with neutrophils from patients in FMF remission and those from control subjects. In Fig 1, A and C, data are presented as means ± SDs. ∗P < .05. Journal of Allergy and Clinical Immunology 2017 140, 1378-1387.e13DOI: (10.1016/j.jaci.2017.02.021) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 REDD1 induction leads to autophagy-mediated NET release. A, Induction of REDD1 in neutrophils from patients in FMF remission compared with neutrophils from control subjects. B and C, REDD1-induced autophagy assessed with LC3B staining (red, LC3B; blue, 4′,6-diamidino-2-phenylindole [DAPI]/DNA; Fig 2, B) or p62/SQSTM1 immunoblotting (Fig 2, C). D and E, REDD1-induced NET release is autophagy mediated. F, Induction of NET release in neutrophils from patients in FMF remission compared with those from control subjects. G, REDD1 expression in neutrophils from control subjects compared with those from patients in FMF remission treated with sera from patients with FMF attacks. H, Induction of NET release in neutrophils from patients in FMF remission. Fig 2, D and H, Green, neutrophil elastase (NE); red, CitH3. In Fig 2, A-H, n = 6. Bars show means ± SDs. ∗P < .05. Journal of Allergy and Clinical Immunology 2017 140, 1378-1387.e13DOI: (10.1016/j.jaci.2017.02.021) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 The microenvironment in patients with FMF attacks is required for IL-1β expression on REDD1-induced NETs. Neutrophils from patients in FMF remission were treated with REDD1 inducer, sera from patients with FMF attacks, and a combination of these, as assessed by means of confocal microscopy (green, IL-1β, red, neutrophil elastase [NE]; A) and immunoblotting of purified NET proteins (B; n = 4). Journal of Allergy and Clinical Immunology 2017 140, 1378-1387.e13DOI: (10.1016/j.jaci.2017.02.021) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Regulation of IL-1β bioactivity by REDD1-induced autolysosomes in neutrophils. A-C, Neutrophils from control subjects (Fig 4, A) or neutrophils from patients in FMF remission (Fig 4, B) treated with sera from patients with FMF attacks in the presence of REDD1 inducer (10 μmol/L) and ex vivo isolated neutrophils from patients with FMF attacks (Fig 4, C; magenta, REDD1; green, pyrin or NALP3; red, LysoTracker). D and E, IL-1β expression in purified NET proteins (Fig 4, D) or on isolated NET structures from neutrophils from control subjects or neutrophils from patients in FMF remission on treatment with sera from patients with FMF attacks in the presence of REDD1 inducer (10 μmol/L; Fig 4, E). F, IL-1β protein expression in PBMCs from control subjects treated with NET structures generated by double-stimulated neutrophils from patients in FMF remission or control subjects. Fig 4, A-F, n = 4. Data are presented as means ± SDs. IOD, Integrated optical density. ∗P < .05. Journal of Allergy and Clinical Immunology 2017 140, 1378-1387.e13DOI: (10.1016/j.jaci.2017.02.021) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Effect of epinephrine in neutrophils from patients in FMF remission. A, REDD1 expression levels in neutrophils treated with epinephrine (1 nmol/L; mean ± SD). B, NET release from neutrophils treated with epinephrine (1 nmol/L) in the presence or absence of sera from patients with FMF attacks (green, IL-1β; red, neutrophil elastase [NE]). Fig 5, A and B, n = 4. ∗P < .05. Journal of Allergy and Clinical Immunology 2017 140, 1378-1387.e13DOI: (10.1016/j.jaci.2017.02.021) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 REDD1 expression in patients with inflammatory diseases. A and B, REDD1 expression in neutrophils from patients with FMF attacks, active AOSD, or acute bacterial infections compared with healthy control subjects (Fig 6, A) and in neutrophils from control subjects treated with corresponding serum (Fig 6, B). Data are presented as means ± SDs. n.s., Not significant. ∗P < .05. C, Heat map analysis of REDD1 expression between neutrophils from selected similarly aged patients (FMF, AOSD, infections) with attack and those from the same patients in remission and after in vitro stimulation of neutrophils from control subjects with corresponding serum. Journal of Allergy and Clinical Immunology 2017 140, 1378-1387.e13DOI: (10.1016/j.jaci.2017.02.021) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Neutrophil IL-1β/CitH3 expression in patients with inflammatory diseases. Representative scatter plots (A) and data from flow cytometry of CitH3-positive and/or IL-1β–positive ex vivo isolated neutrophils from patients with autoinflammatory diseases compared with those from patients with infections or healthy control subjects (B-D). In Fig 7, B and C, data are presented as means ± SDs. n.s., Not significant. ∗P < .05. Journal of Allergy and Clinical Immunology 2017 140, 1378-1387.e13DOI: (10.1016/j.jaci.2017.02.021) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Differentially expressed genes between patients with FMF in remission and control subjects (cutoff false discovery rate < 0.05). β-Tubulin (TUBB) is displayed as a negative control and has no difference of expression. Data are presented as means ± SDs. Journal of Allergy and Clinical Immunology 2017 140, 1378-1387.e13DOI: (10.1016/j.jaci.2017.02.021) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Increase in the autophagy level of neutrophils from patients in FMF remission in the presence of a high dose of REDD1 inducer. Autophagy induction assessed with LC3B staining in neutrophils from patients in FMF remission treated with different doses of REDD1 inducer are shown (confocal microscopy; red, LC3B; blue, 4′,6-diamidino-2-phenylindole [DAPI]/DNA; n = 6). Journal of Allergy and Clinical Immunology 2017 140, 1378-1387.e13DOI: (10.1016/j.jaci.2017.02.021) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 IL-1β protein expression in PBMCs from control subjects treated with NET structures derived from neutrophils from control subjects on treatment with sera from patients with FMF attacks in the presence of REDD1 inducer (10 μmol/L; n = 4). Anakinra was used as an inhibitor of IL-1β signaling. GAPDH, Glyceraldehyde-3-phosphate dehydrogenase. Journal of Allergy and Clinical Immunology 2017 140, 1378-1387.e13DOI: (10.1016/j.jaci.2017.02.021) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Expression of IL-1β on NETs released from neutrophils obtained from patients with AOSD. Localization of IL-1β in NETs from patients with AOSD during active disease compared with those released from patients with bacterial infections is shown (confocal microscopy; green, IL-1β; red, neutrophil elastase [NE]; blue, 4′,6-diamidino-2-phenylindole [DAPI]/DNA; n = 5). Journal of Allergy and Clinical Immunology 2017 140, 1378-1387.e13DOI: (10.1016/j.jaci.2017.02.021) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 IL-1β/CitH3 expression in neutrophils from control subjects stimulated in vitro with sera from patients with FMF attacks or sepsis or healthy control sera. Representative scatter plots (A) and data from flow cytometry of CitH3- or IL-1β–positive neutrophils (B and C) are shown. In Fig E5, B and C, data are presented as means ± SDs. Fig E5, B and C, n = 5. ∗P < .05. Journal of Allergy and Clinical Immunology 2017 140, 1378-1387.e13DOI: (10.1016/j.jaci.2017.02.021) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions