Background: Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death worldwide with no curative therapy. A non-canonical Notch ligand, DNER, has been recently identified in GWAS to associate with COPD severity, but its function and contribution to COPD is unknown.Methods: DNER localisation was assessed in lung tissue from healthy and COPD patients, and cigarette smoke (CS) exposed mice. Microarray analysis was performed on WT and DNER deficient M1 and M2 bone marrow-derived macrophages (BMDM), and gene set enrichment undertaken. WT and DNER deficient mice were exposed to CS or filtered air for 3 day and 2 months to assess IFN gamma-expressing macrophages and emphysema development. Notch and NFKB active subunits were quantified in WT and DNER deficient LPS-treated and untreated BMDM.Findings: Immunofluorescence staining revealed DNER localised to macrophages in lung tissue from COPD patients and mice. Human and murine macrophages showed enhanced DNER expression in response to inflammation. Interestingly, pro-inflammatory DNER deficient BMDMs exhibited impaired NICDI/NFKB dependent IFN gamma signalling and reduced nuclear NICD1/NFKB translocation. Furthermore, decreased IFN gamma production and Notch1 activation in recruited macrophages from CS exposed DNER deficient mice were observed, protecting against emphysema and lung dysfunction.Interpretation: DNER is a novel protein induced in COPD patients and 6 months CS-exposed mice that regulates IFN gamma secretion via non-canonical Notch in pro-inflammatory recruited macrophages. These results provide a new pathway involved in COPD immunity that could contribute to the discovery of innovative therapeutic targets.