MGST2hi PMNs mediate NETs and drive pericyte-to-myofibroblast transition in RA-ILD 

This study identifies MGST2hi (microsomal glutathione S-transferase 2-high) polymorphonuclear neutrophils (PMNs) as key pathogenic drivers of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Using a zymosan A-induced mouse model, the authors found markedly expanded Mgst2hi NET-releasing PMNs in lungs, bronchoalveolar lavage fluid (BALF), and peripheral blood. Pharmacologic inhibition with coniferyl ferulate (CF) and AAV9-shRNA-mediated Mgst2 knockdown suppressed NET formation and attenuated pulmonary fibrotic progression. Mechanistically, Mgst2 promotes NET release via a NOX2-dependent pathway, and the resulting NETs drive pericyte-to-myofibroblast transdifferentiation through the TGF-β pathway. Clinically, Mgst2hi PMNs were significantly elevated in RA-ILD patients, particularly in the NSIP subtype. Their proportion correlated with disease severity as quantified by CT-based fibrosis score, vessel score, and mean lung vessel diameter — assessed using AVIEW Lung Texture (Coreline Soft) for standardized pulmonary CT analysis. These findings suggest Mgst2hi PMNs as a potential therapeutic target in RA-ILD.