Abstract Background Ambient fine particulate matter (PM2.5) increases respiratory-related hospital admissions and is associated with greater morbidity and mortality. Epidemiological evidence indicates that exposure to particulate matter is linked to the development of idiopathic pulmonary fibrosis (IPF) and increases the incidence of acute exacerbations of IPF (AE-IPF). Triggering receptor expressed on myeloid cells (TREM)-1, an immune receptor constitutively expressed by monocytes, macrophages, and neutrophils, regulates monocyte mobilization and amplifies acute inflammatory responses. Here, we determine if TREM-1 is increased in AE-IPF subjects to regulate recruitment of classical monocytes expressing high levels of Ly6C (Ly6Chi) to mediate disease progression. Methods We measured levels of soluble TREM-1 (sTREM-1) in plasma were determined in IPF, AE-IPF, and non-disease control participants. For murine studies, we exposed mice to intratracheal (i.t.) saline or bleomycin to establish fibrosis, followed by daily i.t. PM2.5 or PBS administration for 7 days starting day 21 post-bleomycin. Experiments were conducted in wild-type C57Bl/6 mice and repeated in Trem1-/-Cx3cr1creER monocyte-specific conditional knockouts. BAL cells and lung tissue underwent FACS analysis to distinguish macrophage/monocyte subsets. Adoptive transfer of FACS-sorted Ly6Chi monocytes by i.t. was performed in mice 21 days after exposure to bleomycin. Additionally, precision-cut lung slices (PCLS) were generated from saline or bleomycin-exposed mice and co-cultured with FACS-sorted bone marrow-derived Ly6Chi monocytes. Results Plasma obtained from AE-IPF subjects showed 5-fold increase in sTREM-1 levels compared to stable IPF subjects. sTREM-1 was similarly increased in plasma and BAL cells from our mouse model of PM2.5-mediated AE-IPF. Increased Ly6Chi monocytes in mice with AE-IPF was directly linked with exacerbated fibrosis and greater sTREM-1 levels in the BAL. Surprisingly, Trem1-/-Cx3cr1creER mice showed augmented fibrosis after bleomycin exposure and altered inflammation characterized by increased Ly6Chi monocytes in the BAL. Ly6Chi monocytes isolated from bleomycin-exposed Trem1-/-Cx3cr1creER mice exhibited increased mtROS and mitochondrial content, suggesting heightened metabolic strain and mitochondrial dysfunction occurs in the absence of TREM-1. Moreover, increased collagen 1A1 mRNA was detected in fibrotic PCLS co-cultured with FACS-sorted Ly6Chi monocytes. Conclusion These findings indicate that TREM-1 regulates Ly6Chi monocyte recruitment to drive fibrotic progression by promoting mitochondrial dysfunction. This abstract is funded by: HIA-1438834, I01RD001549
Larson-Casey et al. (Fri,) studied this question.