C29-17 An Emerging Immunomodulatory Role for Nerve and Airway-associated Macrophages (NAMs) in Pulmonary Fibrosis

Rationale Macrophages and monocytes have been implicated in the pathogenesis of pulmonary fibrosis. Pulmonary macrophages have traditionally been classified as alveolar macrophages (AMs) or interstitial macrophages (IMs). Increased monocyte influx into the injured lung to support lung repair and to compensate for depletion of local macrophages but might result in increased inflammation thereby worsening fibrosis formation. We and others have revealed a novel class of pulmonary tissue-resident macrophages - Nerve and Airway-associated Macrophages (NAMs), capable of modulating lung injury repair after H1N1 infection. However, their role in pulmonary fibrosis is unknown. Methods To evaluate the role of NAMs and their effect on monocytes during pulmonary fibrosis, we applied the established lung fibrosis model of bleomycin injury to transgenic mice that allow for selective depletion of NAMs. Results In wildtype mice bleomycin injury resulted in the expected peak in neutrophil and monocyte infiltration during acute lung injury phase. This was followed by a rise in NAMs, AMs, which showed transient loss of Siglec-F expression, and IMs, all of which extended into fibrosis phase and did not recover to baseline levels at resolution. NAM depleted bleomycin-injured mice were sicker than their littermates, displayed greater weight loss, reduced survival, and increased lung weight. NAM depletion resulted in significantly increased CCR2+ monocytic infiltration after bleomycin injury, suggesting greater lung injury with increased depletion of local macrophages driving monocyte influx. However, the phenotypes of infiltrating monocytes were markedly different with a nearly 50% increase in MHC-II+ monocytes and corresponding ∼50% reduction in MHC-II- monocytes. Consistent with these observations, loss of NAMs was associated with increased weight loss, mortality, accompanied by increases in BAL neutrophilia and lymphocytosis, as well as lung fibrotic injury markers when compared to controls, suggesting that depletion of tissue-resident NAMs led to increased lung injury through infiltrating monocytes and worse clinical outcome. Conclusions Our findings provide new insights into the mechanisms that modulate inflammation during pulmonary fibrosis and highlight a potential local immunomodulatory role for NAMs by decreasing influx of bone-marrow derived immune cells into the injured lungs.