IL-36? – a key mediator of neutrophilic inflammation in chronic obstructive pulmonary disease

<b>Introduction:</b> COPD is a chronic inflammatory lung disease, associated with elevated neutrophilic inflammation. The IL-36 family belongs to the IL-1 superfamily consisting of 3 agonists (IL-36α, β, γ) and 2 antagonists (IL-36RA and IL-38); their role in COPD is unclear. Here, we examined their role in COPD, examining the cellular source and effects of these cytokines within the lung. <b>Methods:</b> Human small airway epithelial cells (SAEC), small airway fibroblasts (SAF) and tissue resident macrophages (TMφ) were extract from lung tissue from non-smokers (NS) and COPD patients. Cytokines were measured by ELISA and gene expression by RT-PCR. Lung cells were treated with IL-36γ (100 ng/ml). <b>Results:</b> IL-36γ, but not IL-36α/β, was significantly elevated in bronchoalveolar lavage fluid (p=0.032) and nasal fluid (p=0.042) of COPD patients (n=9-18) compared to NS (n=8-13). IL-36RA was significantly decreased in sputum samples from COPD patients (P=0.006) (n=13). IL-36RA gene expression was significantly decreased in COPD TMφ (n=8) compared to NS (n=5) (p=0.0048); IL-38 was undetectable. SAEC were the major source of IL-36γ (n=8) (P=0.0001). Treatment of TMφ, SAEC and SAF with IL-36γ led to release of the neutrophil chemokines CXCL1/8, as well as IL-6, GM-CSF and MMP-9; SAF released the highest concentrations, suggesting these as major effector cell. <b>Conclusions:</b> These data suggest IL-36γ is elevated within the lungs of COPD patients and released from SAEC. IL-36γ activates SAF to release neutrophil chemokines and MMPs, which can cause disease pathobiology. Loss of IL-36RA may further exacerbate these effects. Inhibitors of IL-36 signalling may prove to be useful anti-inflammatory treatments in COPD.