IL36 receptor (IL36R) signalling is increased in COPD, with increased receptor agonist (IL36γ) and reduced antagonist (IL36RA). IL36γ is released from epithelial cells and activates a pro-inflammatory response by small airway fibroblasts (SAF), but the effect of IL36 signalling on lung macrophages is not fully understood. <b>Methods:</b> Monocyte derived macrophages (MDM) from healthy non-smokers (NS) and COPD patients were incubated with media (NT) or 200ng/ml IL36γ for 24h. MDM were exposed to H.influenzae for 4h and phagocytosis measured by fluorescence. IL6, CXCL1 and CXCL8 were measured in MDM supernatants by ELISA. To assess crosstalk between cell types, supernatants from untreated and IL36γ stimulated SAF were incubated with MDM and phagocytosis and cytokine secretion measured. <b>Results:</b> IL36γ reduced phagocytosis by 23% in COPD MDM (p<0.01, n=13) but there was no effect on healthy MDM (n=9). IL36γ had no direct effect on MDM cytokine secretion. There was no effect of untreated SAF on MDM cytokine secretion. However, IL36γ stimulated SAF caused increased IL6 (NT SAF vs IL36γ SAF: 2.8±0.4 vs 49.6±13.1ng/ml), CXCL1 (3.4±1.5 vs 14.1±4.9ng/ml) and CXCL8 (13.9±3.4 vs 53.3±11.0ng/ml) secretion from both NS and COPD MDM. Pre-treatment of MDM with IL36RA did not affect MDM cytokine secretion (IL6 44.5ng/ml, CXCL8 46.9ng/ml, CXCL1 27.9ng/ml, n=10) suggesting that an intermediate factor released by SAF in response to IL36γ causes the pro-inflammatory effect seen in MDM. <b>Conclusion:</b> Increased levels of IL36γ in COPD impair macrophage phagocytosis and activate fibroblasts that further stimulate macrophage inflammatory mediator release. As IL36γ is upregulated by viruses, these results may be clinically relevant for acute COPD exacerbations.
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