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

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Title: Imbalance between IL-36 receptor agonist and antagonist drives neutrophilic inflammation in COPD
Authors: Baker, JR
Fenwick, PS
Koss, CK
Owles, HB
Elkin, SL
Fine, JS
Thomas, M
Kasmi, KC
Barnes, PJ
Donnelly, LE
Item Type: Journal Article
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 to control subjects. IL-36γ is derived from small airway epithelial cells (SAEC) and 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, that was inhibited by exogenous IL-36RA. The use of a therapeutic antibody that inhibits binding to the IL-36 receptor (IL-36R) attenuated IL-36γ driven inflammation and cellular cross talk. We have demonstrated a mechanism for the amplification and propagation of neutrophilic inflammation in COPD and that blocking this cytokine family via a IL-36R neutralizing antibody could be a promising new therapeutic strategy in the treatment of COPD.
Issue Date: 8-Aug-2022
Date of Acceptance: 1-Jun-2022
URI: http://hdl.handle.net/10044/1/97997
DOI: 10.1172/jci.insight.155581
ISSN: 2379-3708
Publisher: American Society for Clinical Investigation
Journal / Book Title: JCI Insight
Volume: 7
Issue: 15
Copyright Statement: © 2022 The Author(s). This article is published under CC BY 4.0 International licence (http://creativecommons.org/licenses/by/4.0/)
Keywords: COPD
Cell Biology
Cellular immune response
Cytokines
Pulmonology
Cytokines
Humans
Inflammation
Interleukin-1
Interleukins
Pulmonary Disease, Chronic Obstructive
Humans
Pulmonary Disease, Chronic Obstructive
Inflammation
Interleukins
Interleukin-1
Cytokines
COPD
Cell Biology
Cellular immune response
Cytokines
Pulmonology
Publication Status: Published
Conference Place: United States
Online Publication Date: 2022-06-28
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine



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