Therapeutic Targeting of the IL-6 Trans-Signaling/Mechanistic Target of Rapamycin Complex 1 Axis in Pulmonary Emphysema

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, Brendan J Jenkins

The potent immunomodulatory cytokine interleukin (IL)-6 is consistently upregulated in human lungs with emphysema, and in mouse emphysema models; however, the mechanism(s) by which IL-6 promotes emphysema remains obscure. IL-6 signals using two distinct modes, classical signalling via its membrane-bound IL-6 receptor (mIL-6R), and trans-signalling via a naturally-occurring soluble IL-6R (sIL-6R). To identify whether IL-6 trans-signalling and/or classical signalling contribute to the pathogenesis of emphysema. We utilized 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 TUNEL assay was employed to assess alveolar cell apoptosis. In mouse and human lung tissues, the expression level and location of IL-6 signalling-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. Lung tissues from emphysema patients, as well as from spontaneous and cigarette smoke-induced emphysema mouse models, were characterized by excessive production of sIL-6R. Genetic blockade of IL-6 trans-signalling in emphysema mouse models, and therapy with the IL-6 trans-signalling antagonist sgp130Fc, ameliorated emphysema by suppressing augmented alveolar type II cell apoptosis. Furthermore, IL-6 trans-signalling-driven emphysematous changes in the lung correlated with mammalian target of rapamycin complex 1 (mTORC1) hyper-activation, and treatment of emphysema mouse models with the mTORC1 inhibitor rapamycin attenuated emphysematous changes. Collectively, our data reveal that specific targeting of IL-6 trans-signalling may represent a novel treatment strategy for emphysema.