Nuclear Factor Erythroid 2-Related Factor 2 in Chronic Obstructive Pulmonary Disease Progression: Regulation of...

Alveolar microenvironment-driven macrophage polarization critically influences chronic obstructive pulmonary disease (COPD) progression. Nuclear factor erythroid 2-related factor 2 (NRF2), a key transcription factor, regulates macrophage polarization, suppresses inflammation, and promotes cellular repair. However, its role in macrophage-mediated inflammation and metabolic regulation, particularly hyaluronic acid (HA)-related remodeling, remains incompletely defined. This study investigates a novel dimension of NRF2 in COPD pathogenesis through macrophage-specific modulation, aiming to uncover its previously unrecognized mechanism.

Macrophage-specific Nrf2 knockout (KO) and control mice were chronically exposed to cigarette smoke (CS) to induce COPD-like pathology. Lung function, alveolar damage, macrophage polarization (M1/M2), and inflammatory cytokines were analyzed by respiratory function tests, histology, immunohistochemistry, and chemokine profiling, respectively. Proteomics approaches were used to identify dysregulated pathways.

Nrf2 KO mice displayed aggravated CS-induced lung dysfunction and alveolar destruction compared with control mice, accompanied by heightened M1 polarization and elevated pro-inflammatory cytokines (C-C motif chemokine ligand [CCL]2, CCL7, CXCL16). Proteomics revealed dysregulation of immune, oxidative stress, and metabolic pathways in the lungs of KO mice, including HA metabolism/uptake-associated proteins and increased CD44/CD74 expression. These findings suggest an association between NRF2 deficiency, macrophage polarization imbalance, and HA-related remodeling.

Macrophage-specific NRF2 protects against CS-induced COPD-like lung injury by restraining inflammatory activation and preserving macrophage polarization-associated balance. Proteomic and validation analyses further nominate HA metabolism-related remodeling, particularly the CD44/CD74-associated response, as a biologically plausible feature of NRF2-deficient disease progression. These findings define a macrophage NRF2-linked inflammatory-remodeling axis in COPD-like pathology while highlighting the need for functional studies to establish whether HA/CD44 signaling is a causal downstream mechanism.