FSTL-1 Attenuation Causes Spontaneous Smoke-Resistant Pulmonary Emphysema.

Abstract

<b>Rationale:</b> The role of FSTL-1 (follistatin-like 1) in lung homeostasis is unknown.<b>Objectives:</b> We aimed to define the impact of FSTL-1 attenuation on lung structure and function and to identify FSTL-1-regulated transcriptional pathways in the lung. Further, we aimed to analyze the association of FSTL-1 SNPs with lung disease.<b>Methods:</b> FSTL-1 hypomorphic (FSTL-1 Hypo) mice underwent lung morphometry, pulmonary function testing, and micro-computed tomography. <i>Fstl1</i> expression was determined in wild-type lung cell populations from three independent research groups. RNA sequencing of wild-type and FSTL-1 Hypo mice identified FSTL-1-regulated gene expression, followed by validation and mechanistic <i>in vitro</i> examination. <i>FSTL1</i> SNP analysis was performed in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort.<b>Measurements and Main Results:</b> FSTL-1 Hypo mice developed spontaneous emphysema, independent of smoke exposure. <i>Fstl1</i> is highly expressed in the lung by mesenchymal and endothelial cells but not immune cells. RNA sequencing of whole lung identified 33 FSTL-1-regulated genes, including <i>Nr4a1</i>, an orphan nuclear hormone receptor that negatively regulates NF-κB (nuclear factor-κB) signaling. <i>In vitro</i>, recombinant FSTL-1 treatment of macrophages attenuated NF-κB p65 phosphorylation in an <i>Nr4a1</i>-dependent manner. Within the COPDGene cohort, several SNPs in the <i>FSTL1</i> region corresponded to chronic obstructive pulmonary disease and lung function.<b>Conclusions:</b> This work identifies a novel role for FSTL-1 protecting against emphysema development independent of smoke exposure. This FSTL-1-deficient emphysema implicates regulation of immune tolerance in lung macrophages through <i>Nr4a1</i>. Further study of the mechanisms involving FSTL-1 in lung homeostasis, immune regulation, and NF-κB signaling may provide additional insight into the pathophysiology of emphysema and inflammatory lung diseases.