The non-canonical Notch ligand DNER regulates IFNγ in macrophages during COPD progression

ABSTRACT: Chronic Obstructive Pulmonary Diseases (COPD) is the third leading cause of death worldwide with no curative therapy available. A novel non-canonical Notch ligand, DNER, has been identified in a GWAS to correlate with disease severity, but its function and contribution to COPD is completely unknown. DNER localization and expression was determined in COPD patients and 6 month cigarette smoke (CS)-exposed mice. Microarray and GSEA of M1 and M2 bone marrow-derived macrophages (BMDM) from wild type (WT) and Dner deficient mice were performed. IFNγ levels and Notch activation were evaluated in 2 month CS-exposed WT and Dner deficient mice. Notch and NFκB pathways were evaluated by qPCR and Western Blot in BMDM. DNER was increased in the lung of COPD patients and localized to macrophages in human and murine lung tissue. Upon pro-inflammatory conditions, WT BMDM and human macrophages exhibited increased Dner levels. Interestingly, IFNγ responses were abrogated in Dner deficient pro-inflammatory macrophages both in vitro and in vivo. LPS treated Dner deficient BMDM failed to trigger NFκB and Notch signalling cascades evidenced by the absence of nuclear active forms. We provide the first molecular and functional insights into DNER, a novel Notch ligand that controls IFNγ secretion in lung recruited pro-inflammatory macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE119257 | GEO | 2019/03/19

REPOSITORIES: GEO