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 9

Optimization of therapeutic IL-36R inhibition experiments.

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Optimization of therapeutic IL-36R inhibition experiments. (A) Schematic...
(A) Schematic of experimental procedure. (B) Small airway fibroblast (n = 6) were treated with diluted media, media + poly(I:C), conditioned media alone from SAEC, or conditioned media from poly(I:C)–treated SAEC (ranging from 10- to 200-fold) for 24 hours (pooled media from 3 patients with COPD). CXCL1 levels were then measured. (C) Small airway fibroblasts (n = 4) were treated with diluted (ranging from 10- to 200-fold) conditioned media alone from SAEC or conditioned media from poly(I:C)–treated SAEC that had and hadn’t been boiled for 24 hours. CXCL1 levels were then measured. (D) Small airway fibroblast (n = 6) were treated with diluted (ranging from 10- to 200-fold) conditioned media alone from SAEC or conditioned media from poly(I:C)–treated SAEC (ranging from 10- to 200-fold) with or without pretreatment for 2 hours with recombinant IL-36Ra (100 ng/mL). CXCL1 levels were then measured. (E) Small airway fibroblast (n = 4) were pretreated for 2 hours with isotype control (IgG1) antibody or a IL-36R neutralizing antibody and then treated with 100 ng/mL of IL-36γ for 24 hours. (F) Small airway fibroblasts (n = 7) were treated with diluted (ranging from 10- to 200-fold) conditioned media alone from SAEC or conditioned media from poly(I:C)–treated SAEC with pretreatment with either isotype control (IgG1) antibody or a IL-36R neutralizing antibody for 2 hours. CXCL1 levels were then measured. Data are presented as mean ± SEM analyzed by either Kruskal-Wallis with post hoc Dunn’s test (B, C, and E) or Wilcoxon matched-pairs signed-rank test (D and F); *P < 0.05, **P < 0.01.