A74-44 Neddylation-Mediated Regulation of Macrophage Activation in Pulmonary Fibrosis

Rationale

Pulmonary fibrosis is a progressive and often fatal interstitial lung disease characterized by excessive extracellular matrix deposition and irreversible tissue remodeling. Macrophages play a central role in fibrotic progression, particularly through alternative (M2) activation. Neddylation, a ubiquitin-like post-translational modification mediated by NEDD8 conjugation, regulates multiple cellular signaling pathways; however, its role in macrophage activation and pulmonary fibrosis remains poorly defined.

Methods

To investigate the role of neddylation in macrophage-mediated pulmonary fibrosis, myeloid-specific neddylation deficiency was established using LysM-Cre-mediated genetic disruption of a core neddylation component in mice. Pulmonary fibrosis was induced by intratracheal bleomycin administration. Lung injury and fibrosis were assessed by histopathological staining and collagen deposition analysis. Macrophage accumulation and polarization were evaluated using immunofluorescence staining, flow cytometry, and gene expression analyses. Mechanistic signaling pathways were further examined in primary macrophages using immunoblotting.

Results

Myeloid-specific inhibition of neddylation markedly aggravated bleomycin-induced pulmonary fibrosis, as demonstrated by enhanced collagen deposition and more severe lung architectural distortion. Neddylation-deficient macrophages exhibited a pronounced shift toward an alternatively activated phenotype, with significantly increased expression of M2-associated markers, including arginase-1 and CD206. This phenotypic shift was accompanied by altered intracellular signaling favoring profibrotic immune responses. Increased accumulation of M2-like macrophages was observed in fibrotic lung tissue and correlated with disease severity.

Conclusion

These findings identify myeloid neddylation as a critical negative regulator of macrophage alternative activation and fibrotic lung remodeling. Loss of neddylation promotes a profibrotic macrophage phenotype and exacerbates pulmonary fibrosis. Targeting macrophage neddylation may represent a novel therapeutic strategy for the treatment of pulmonary fibrosis.

This abstract is funded by: None