IL-36 receptor agonist and antagonist imbalance drives neutrophilic inflammation in COPD
Jonathan R. Baker, Peter S. Fenwick, Carolin K. Koss, Harriet B. Owles, Sarah L. Elkin, Jay Fine, Matthew Thomas, Karim C. El Kasmi, Peter J. Barnes, Louise E. Donnelly
Jonathan R. Baker, Peter S. Fenwick, Carolin K. Koss, Harriet B. Owles, Sarah L. Elkin, Jay Fine, Matthew Thomas, Karim C. El Kasmi, Peter J. Barnes, Louise E. Donnelly
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Research Article Cell biology Pulmonology

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

Abstract

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-36γ and decreased IL-36 receptor antagonist (IL-36Ra) in bronchoalveolar and nasal fluid compared with control subjects. IL-36γ is derived from small airway epithelial cells (SAEC) and is further induced by a viral mimetic, whereas IL-36Ra is derived from macrophages. IL-36γ 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-36γ, 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-36γ–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.

Authors

Jonathan R. Baker, Peter S. Fenwick, Carolin K. Koss, Harriet B. Owles, Sarah L. Elkin, Jay Fine, Matthew Thomas, Karim C. El Kasmi, Peter J. Barnes, Louise E. Donnelly

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Figure 10

Schematic outlining the role of IL-36γ in COPD pathophysiology.

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Schematic outlining the role of IL-36γ in COPD pathophysiology. Small ai...
Small airway epithelial cells are a major source of IL-36γ in the COPD lung, and the release of IL-36γ is elevated at baseline in these patients. These elevated levels can be exacerbated by viral infection, which may be perpetuated in those who smoke. The resultant pro–IL-36γ is cleaved by neutrophil-derived proteases such as cathepsin G and proteinase-3, generating the active form of IL-36γ. This acts on small airway fibroblasts, leading to the release of MMP2 and MMP9, as well as leading to expression of the chemokines CXCL1 and CXCL8. CXCL1 and CXCL8 recruit neutrophils and perpetuate the cycle of neutrophilic inflammation. This process is amplified in patients with COPD due to the loss of the endogenous IL-36 receptor, IL-36Ra, from macrophages. The released elastases and MMPs contribute to all 3 pathophysiological features of COPD, small airway remodeling, emphysema, and mucous hypersecretion.