Extracellular vimentin promotes neutrophil-dominant granulomatous inflammation in progressive pulmonary sarcoidosis.

Pulmonary sarcoidosis has a heterogeneous clinical course, with a subset of patients progressing to chronic disease and fibrosis despite first-line corticosteroid therapy. The mechanisms driving disease progression are poorly understood, although limited evidence suggests a role for neutrophils. The present study aimed to characterise neutrophils and neutrophil effector molecules in progressive pulmonary sarcoidosis. We first performed in silico transcriptomic analyses to evaluate neutrophil gene signatures in granulomatous lung tissue from patients with progressive, fibrotic sarcoidosis compared with self-resolving disease. In parallel, we employed vimentin-induced mouse models and performed single-cell RNA-sequencing (scRNA-seq), flow cytometry, and immunostaining to examine neutrophils and assess their contribution to lung injury and fibrosis. Neutrophil gene signatures were significantly enriched in progressive sarcoidosis and positively associated with fibrosis-related pathways while inversely correlating with lung function. In the vimentin-induced model, scRNA-seq, flow cytometry, and bronchoalveolar lavage (BAL) differential analyses demonstrated neutrophil infiltration with altered transcriptomic profile and enhanced activation, which were amplified by repeated vimentin challenge. BAL myeloperoxidase activity and total protein, markers of neutrophil activation and lung injury, were significantly elevated and correlated with neutrophil content. Within granulomas, neutrophils were also abundant and neutrophil extracellular traps (NETs) were identified, along with the detection of collagen deposition and fibroblast activation. Together, these findings demonstrate that activation of neutrophil-driven inflammatory pathways is a prominent feature of progressive pulmonary sarcoidosis and can be triggered by extracellular vimentin. Its strong association with lung injury and fibrosis highlights neutrophils and NETosis as potential therapeutic targets for modifying disease trajectory in progressive sarcoidosis.