• Saleela M Ruwanpura, Louise McLeod, Lovisa F Dousha, Huei J Seow, Sultan Alhayyani, Michelle D Tate, Virginie Deswaerte, Gavin D Brooks, Steven Bozinovski, Martin MacDonald, Christoph Garbers, Paul T King, Philip G Bardin, Ross Vlahos, Stefan Rose-John, Gary P Anderson, and Brendan J Jenkins.
• 1 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
• Am. J. Respir. Crit. Care Med. 2016 Dec 15; 194 (12): 1494-1505.

RationaleThe 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.ObjectivesTo identify whether IL-6 trans-signaling and/or classical signaling contribute to the pathogenesis of emphysema.MethodsWe 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 ResultsLung 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.ConclusionsCollectively, our data reveal that specific targeting of IL-6 trans-signaling may represent a novel treatment strategy for emphysema.

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