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Here, we show that COPD subjects have increased IL-36\u03b3 and decreased IL-36 receptor antagonist (IL-36Ra) in bronchoalveolar and nasal fluid compared with control subjects. IL-36\u03b3 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\u03b3 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\u03b3, 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\u03b3\u2013driven 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.<\/jats:p>","DOI":"10.1172\/jci.insight.155581","type":"journal-article","created":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T13:32:11Z","timestamp":1656423131000},"source":"Crossref","is-referenced-by-count":27,"title":["IL-36 receptor agonist and antagonist imbalance drives neutrophilic inflammation in COPD"],"prefix":"10.1172","volume":"7","author":[{"given":"Jonathan R.","family":"Baker","sequence":"first","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter S.","family":"Fenwick","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolin K.","family":"Koss","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH & Co. 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