Saleela M Ruwanpura1,2, Louise McLeod1,2, Lovisa F Dousha3, Huei J Seow3, Sultan Alhayyani1,2, Michelle D Tate1,2, Virginie Deswaerte1,2, Gavin D Brooks1,2, Steven Bozinovski3,4, Martin MacDonald5, Christoph Garbers6, Paul T King1,5, Philip G Bardin1,5, Ross Vlahos3,4, Stefan Rose-John6, Gary P Anderson3, Brendan J Jenkins1,2. 1. 1 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia. 2. 2 Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia. 3. 3 Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria, Australia. 4. 4 School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology University, Bundoora, Victoria, Australia. 5. 5 Monash Lung and Sleep, Monash Medical Centre, Victoria, Australia; and. 6. 6 Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
Abstract
RATIONALE: The potent immunomodulatory cytokine IL-6 is consistently up-regulated in human lungs with emphysema and in mouse emphysema models; however, the mechanisms by which IL-6 promotes emphysema remain obscure. IL-6 signals using two distinct modes: classical signaling via its membrane-bound IL-6 receptor (IL-6R), and trans-signaling via a naturally occurring soluble IL-6R. OBJECTIVES: To identify whether IL-6 trans-signaling and/or classical signaling contribute to the pathogenesis of emphysema. METHODS: We used the gp130F/F genetic mouse model for spontaneous emphysema and cigarette smoke-induced emphysema models. Emphysema in mice was quantified by various methods including in vivo lung function and stereology, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to assess alveolar cell apoptosis. In mouse and human lung tissues, the expression level and location of IL-6 signaling-related genes and proteins were measured, and the levels of IL-6 and related proteins in sera from emphysematous mice and patients were also assessed. MEASUREMENTS AND MAIN RESULTS: Lung tissues from patients with emphysema, and from spontaneous and cigarette smoke-induced emphysema mouse models, were characterized by excessive production of soluble IL-6R. Genetic blockade of IL-6 trans-signaling in emphysema mouse models and therapy with the IL-6 trans-signaling antagonist sgp130Fc ameliorated emphysema by suppressing augmented alveolar type II cell apoptosis. Furthermore, IL-6 trans-signaling-driven emphysematous changes in the lung correlated with mechanistic target of rapamycin complex 1 hyperactivation, and treatment of emphysema mouse models with the mechanistic target of rapamycin complex 1 inhibitor rapamycin attenuated emphysematous changes. CONCLUSIONS: Collectively, our data reveal that specific targeting of IL-6 trans-signaling may represent a novel treatment strategy for emphysema.
RATIONALE: The potent immunomodulatory cytokine IL-6 is consistently up-regulated in human lungs with emphysema and in mouseemphysema models; however, the mechanisms by which IL-6 promotes emphysema remain obscure. IL-6 signals using two distinct modes: classical signaling via its membrane-bound IL-6 receptor (IL-6R), and trans-signaling via a naturally occurring soluble IL-6R. OBJECTIVES: To identify whether IL-6 trans-signaling and/or classical signaling contribute to the pathogenesis of emphysema. METHODS: We used the gp130F/F genetic mouse model for spontaneous emphysema and cigarette smoke-induced emphysema models. Emphysema in mice was quantified by various methods including in vivo lung function and stereology, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to assess alveolar cell apoptosis. In mouse and human lung tissues, the expression level and location of IL-6 signaling-related genes and proteins were measured, and the levels of IL-6 and related proteins in sera from emphysematous mice and patients were also assessed. MEASUREMENTS AND MAIN RESULTS: Lung tissues from patients with emphysema, and from spontaneous and cigarette smoke-induced emphysemamouse models, were characterized by excessive production of soluble IL-6R. Genetic blockade of IL-6 trans-signaling in emphysemamouse models and therapy with the IL-6 trans-signaling antagonist sgp130Fc ameliorated emphysema by suppressing augmented alveolar type II cell apoptosis. Furthermore, IL-6 trans-signaling-driven emphysematous changes in the lung correlated with mechanistic target of rapamycin complex 1 hyperactivation, and treatment of emphysemamouse models with the mechanistic target of rapamycin complex 1 inhibitor rapamycin attenuated emphysematous changes. CONCLUSIONS: Collectively, our data reveal that specific targeting of IL-6 trans-signaling may represent a novel treatment strategy for emphysema.
Authors: Saleela M Ruwanpura; Louise McLeod; Lovisa F Dousha; Huei J Seow; Alison C West; Alice J West; Teresa Weng; Mohammad Alanazi; Martin MacDonald; Paul T King; Philip G Bardin; Cem Gabay; Dennis M Klinman; Steven Bozinovski; Ross Vlahos; Gary P Anderson; Stefan Rose-John; Mohamed I Saad; Brendan J Jenkins Journal: Proc Natl Acad Sci U S A Date: 2022-08-29 Impact factor: 12.779
Authors: Neda Farahi; Ellie Paige; Jozef Balla; Emily Prudence; Ricardo C Ferreira; Mark Southwood; Sarah L Appleby; Per Bakke; Amund Gulsvik; Augusto A Litonjua; David Sparrow; Edwin K Silverman; Michael H Cho; John Danesh; Dirk S Paul; Daniel F Freitag; Edwin R Chilvers Journal: Hum Mol Genet Date: 2017-04-15 Impact factor: 6.150