T Cell-Derived IL-17 Mediates Epithelial Changes in the Airway and Drives Pulmonary Neutrophilia
Laura K Fogli,Mark S. Sundrud,Swati Goel,Sofia Bajwa,Kari Jensen,Emmanuel Derudder,Amy Sun,Maryaline Coffre,Catherine Uyttenhove,Jacques Van Snick,Marc Schmidt-Supprian,Anjana Rao,Gabriele Grunig,Joan E. Durbin,Stefano Casola,Klaus Rajewsky,Sergei B. Koralov +16 more
Reads0
Chats0
TLDR
A novel mouse model of spontaneous IL-17–driven lung inflammation that exhibits many similarities to asthma in humans is described and it is found that STAT3 hyperactivity in T lymphocytes causes an expansion of Th17 cells, which home preferentially to the lungs.Abstract:
Th17 cells are a proinflammatory subset of effector T cells that have been implicated in the pathogenesis of asthma. Their production of the cytokine IL-17 is known to induce local recruitment of neutrophils, but the direct impact of IL-17 on the lung epithelium is poorly understood. In this study, we describe a novel mouse model of spontaneous IL-17-driven lung inflammation that exhibits many similarities to asthma in humans. We have found that STAT3 hyperactivity in T lymphocytes causes an expansion of Th17 cells, which home preferentially to the lungs. IL-17 secretion then leads to neutrophil infiltration and lung epithelial changes, in turn leading to a chronic inflammatory state with increased mucus production and decreased lung function. We used this model to investigate the effects of IL-17 activity on airway epithelium and identified CXCL5 and MIP-2 as important factors in neutrophil recruitment. The neutralization of IL-17 greatly reduces pulmonary neutrophilia, underscoring a key role for IL-17 in promoting chronic airway inflammation. These findings emphasize the role of IL-17 in mediating neutrophil-driven pulmonary inflammation and highlight a new mouse model that may be used for the development of novel therapies targeting Th17 cells in asthma and other chronic pulmonary diseases.read more
Citations
More filters
Journal ArticleDOI
Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation
Katharina M. Jeltsch,Desheng Hu,Sven Brenner,Jessica Zöller,Gitta Anne Heinz,Daniel Nagel,Katharina U. Vogel,Nina Rehage,Sebastian C. Warth,Stephanie L. Edelmann,Renee Gloury,Nina A. Martin,Claudia Lohs,Maciej Lech,Jenny E. Stehklein,Arie Geerlof,Elisabeth Kremmer,Achim Weber,Hans-Joachim Anders,Ingo Schmitz,Marc Schmidt-Supprian,Mingui Fu,Helmut Holtmann,Daniel Krappmann,Jürgen Ruland,Axel Kallies,Mathias Heikenwalder,Vigo Heissmeyer +27 more
TL;DR: This pathway acts as a 'rheostat' by translating TCR signal strength via graded inactivation of post-transcriptional repressors and differential derepression of targets to enhance TH17 differentiation.
Journal ArticleDOI
CXCL5 Drives Neutrophil Recruitment in TH17-Mediated GN
Erik Disteldorf,Christian Krebs,Hans-Joachim Paust,Jan-Eric Turner,Geraldine Nouailles,André P. Tittel,Catherine Meyer-Schwesinger,Gesa Stege,Silke R. Brix,Joachim Velden,Thorsten Wiech,Udo Helmchen,Oliver M. Steinmetz,Anett Peters,Sabrina B. Bennstein,Anna Kaffke,Chrystel Llanto,Sergio A. Lira,Hans-Willi Mittrücker,Rolf A.K. Stahl,Christian Kurts,Stefan H. E. Kaufmann,Ulf Panzer +22 more
TL;DR: CXCL5 expression was highly upregulated in the kidneys of patients with ANCA-associated crescentic GN as opposed to patients with acute bacterial pyelonephritis, identifying it as a potential therapeutic target for the restriction of pathogenic neutrophil infiltration in TH17-mediated autoimmune diseases while leaving intact the neutrophils function in protective immunity against invading pathogens.
Journal ArticleDOI
CRAC Channels and Calcium Signaling in T Cell-Mediated Immunity.
TL;DR: New insights are examined into how CRAC channels control T cell-mediated immunity and studies in mice lacking Stim and Orai genes have illuminated many cellular and molecular mechanisms by which these molecules control lymphocyte function.
Journal ArticleDOI
Lactobacillus acidophilus Suppresses Colitis-Associated Activation of the IL-23/Th17 Axis
TL;DR: Results showed that administration of L. acidophilus suppressed Th17 cell-mediated secretion of proinflammatory cytokine IL-17 through downregulation of IL-23 and TGFβ1 expression and downstream phosphorylation of p-STAT3.
Journal ArticleDOI
Mitochondrial Oxidative Phosphorylation Regulates the Fate Decision between Pathogenic Th17 and Regulatory T Cells.
Boyoung Shin,Gloria A. Benavides,Jianlin Geng,Sergei B. Koralov,Hui Hu,Victor M. Darley-Usmar,Laurie E. Harrington +6 more
TL;DR: The data reveal a regulatory role of mitochondrial OXPHOS in dictating the fate decision between Th17 and Treg cells by supporting early molecular events necessary for Th17 commitment.
References
More filters
Journal ArticleDOI
A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17
Heon Park,Zhaoxia Li,Xuexian O. Yang,Seon Hee Chang,Roza Nurieva,Yi Hong Wang,Ying Wang,Leroy Hood,Zhou Zhu,Qiang Tian,Chen Dong +10 more
TL;DR: In vivo, antibody to IL- 17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused Chemokine production and leukocyte infiltration, indicating a unique T helper lineage that regulates tissue inflammation.
Journal ArticleDOI
Stat3 as an Oncogene
Jacqueline Bromberg,Melissa H. Wrzeszczynska,Geeta Devgan,Yanxiang Zhao,Richard G. Pestell,Chris Albanese,James E. Darnell +6 more
TL;DR: Substitution of two cysteine residues within the C-terminal loop of the SH2 domain of Stat3 produces a molecule that dimerizes spontaneously, binds to DNA, and activates transcription.
Journal ArticleDOI
Stat3 regulates cytokine-mediated generation of inflammatory helper t cells
Xuexian O. Yang,Athanasia D. Panopoulos,Roza Nurieva,Seon Hee Chang,Demin Wang,Stephanie S. Watowich,Chen Dong +6 more
TL;DR: A pathway whereby cytokines regulate THi differentiation through a selective STAT transcription factor that functions to regulate lineage-specific gene expression is demonstrated.
Journal ArticleDOI
Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses
Susumu Nakae,Yutaka Komiyama,Aya Nambu,Katsuko Sudo,Michiko Iwase,Ikuo Homma,Kenji Sekikawa,Masahide Asano,Masahide Asano,Yoichiro Iwakura +9 more
TL;DR: It is found that contact, delayed-type, and airway hypersensitivity responses, as well as T-dependent antibody production, were significantly reduced in the mutant mice, while IL-17 deficiency of donor T cells did not affect acute graft-versus-host reaction.
Journal ArticleDOI
The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF.
Mohamed El-Behi,Bogoljub Ciric,Hong Dai,Yaping Yan,Melissa Cullimore,Farinaz Safavi,Guang-Xian Zhang,Bonnie N. Dittel,Abdolmohamad Rostami +8 more
TL;DR: Cross-regulation of IL-23 and GM- CSF explains the similar pattern of resistance to autoimmunity when either of the two cytokines is absent and identifies TH17 cells as a crucial source of GM-CSF in autoimmune inflammation.