Therapeutic targeting of the IL-6 transsignalling in pulmonary emphysema.

Abstract

Background and Aims: Emphysema is the major debilitating component of COPD, the 4th leading cause of death worldwide with no current treatments. Lung inflammation triggered by exposure to environmental factors (tobacco) is strongly linked to emphysema. My research has discovered that expression of interleukin (IL)-6 is consistently increased in emphysema patients, and in a genetic mouse model for spontaneous emphysema (gp130F/F) to drive the onset of emphysema. Although IL-6 signals using 2 distinct modes, classical signalling via its membrane-bound IL-6 receptor, and trans-signalling (TS) via a naturally-occurring soluble IL-6R (sIL-6R), the precise mechanism(s) by which IL-6 promotes emphysema remains to be elucidated. Our aim is to identify IL-6TS mediated emphysematous molecular/cellular processes. Method(s): The genetic and therapeutic blockade of gp130F/F emphysema mouse model was used to prove the specific role of IL-6TS in driving disease. Emphysema patient lung biopsies and serum during stable disease, with their own corresponding acute exacerbation samples were used for identifying IL-6TS in human emphysema development and exacerbations. Result(s): Here, we demonstrate that lung tissues and serum from emphysema patients, as well as from spontaneous (gp130F/F) and cigarette smoke-induced emphysema mouse models, are characterized by excessive production of the soluble IL-6 receptor, which is essential for pathogenic IL-6TS. Genetic and therapeutic blockade of IL-6TS in emphysema mouse models with the antagonist sgp130Fc prevented emphysema by suppressing augmented alveolar type II cell apoptosis. Finally, we also reveal that IL-6TS components are up-regulated in serum from emphysema patients during exacerbation. Conclusion(s): Collectively, we define that hyper-activation of the IL-6TS components in the lung augment cell apoptosis, which in turn cause emphysema. These data have considerable translational potential for biomarker discovery and early disease detection, as well as patient stratification for potential responders that may gain the most benefit from selective anti-IL-6TS directed therapies during development and exacerbation.