Enhanced CCL2–CCR2 signalling promotes recruitment of monocyte-derived macrophages in progressive fibrosing hypersensitivity pneumonitis

Hypersensitivity pneumonitis is characterized by immune dysregulation that often leads to irreversible lung tissue scarring. While elevated monocytes play a key role in idiopathic pulmonary fibrosis, their contribution in progressive fibrotic hypersensitivity pneumonitis, along with the role of the CCL2 chemoattractant, requires clarification. Immune characterization of circulating and lung markers of 71 patients with fibrotic hypersensitivity pneumonitis with median follow-up time of 35.8 months (57.7% progressed, 31% exacerbated), comparing with controls, non-fibrotic cases and idiopathic pulmonary fibrosis. Elevated serum CCL2 strongly associated with disease progression and acute exacerbations, with baseline levels above 1080 pg/mL predicting progression and shorter survival. Despite significant variability in CCL2 levels over time, their elevation near progression was consistent, suggesting a role for this chemokine in the fibrotic cascade. Moreover, classical monocytes from patients with progressive disease displayed higher CCR2 expression, and peripheral blood mononuclear cells from these patients showed enhanced CCL2-driven chemotaxis. Bronchoalveolar lavage immunophenotyping identified enriched CCR2 + monocyte-derived precursors in fibrotic hypersensitivity pneumonitis, implicating this cellular population in disease severity. Genetic analysis of CCL2/CCR2 revealed no association between their expression and known polymorphisms. Mechanistically, elevated CCL2 may drive disease progression by recruiting CCR2 + monocytes, contributing to the profibrotic microenvironment. These findings underscore the CCL2/CCR2 axis as a promising biomarker pathway for disease monitoring in fibrotic hypersensitivity pneumonitis, which could guide therapeutic interventions and stratification of high-risk patients.