IL-36 receptor agonist and antagonist imbalance drives neutrophilic inflammation in COPD

Current treatments fail to modify the underlying pathophysiology and disease progression of chronic obstructive pulmonary disease (COPD), necessitating alternative therapies. Here, we show that COPD subjects have increased IL-36?? and decreased IL-36 receptor antagonist (IL-36Ra) in bronchoalveolar and nasal fluid compared with control subjects. IL-36?? is derived from small airway epithelial cells (SAEC) and is further induced by a viral mimetic, whereas IL-36Ra is derived from macrophages. IL-36?? stimulates release of the neutrophil chemoattractants CXCL1 and CXCL8, as well as elastolytic matrix metalloproteinases (MMPs) from small airway fibroblasts (SAF). Proteases released from COPD neutrophils cleave and activate IL-36??, thereby perpetuating IL-36 inflammation. Transfer of culture media from SAEC to SAF stimulated release of CXCL1, which was inhibited by exogenous IL-36Ra. The use of a therapeutic antibody that inhibits binding to the IL-36R attenuated IL-36?????driven inflammation and cellular crosstalk. We have demonstrated a mechanism for the amplification and propagation of neutrophilic inflammation in COPD and have shown that blocking this cytokine family via a IL-36R neutralizing antibody could be a promising therapeutic strategy in the treatment of COPD.

Automated summary

Current treatments for chronic obstructive pulmonary disease (COPD) are unable to modify the underlying pathophysiology and disease progression, necessitating the search for alternative therapies. This study reveals that COPD patients have increased levels of IL-36α and decreased levels of IL-36 receptor antagonist (IL-36Ra) in bronchoalveolar and nasal fluid. IL-36α stimulates the release of CXCL1, which can be inhibited by exogenous IL-36Ra, suggesting that blocking IL-36R could attenuate COPD-induced inflammation.