FSTL-1 Attenuation Causes Spontaneous Smoke-Resistant Pulmonary Emphysema

Abstract

Rationale: The role of FSTL-1 (follistatin-like 1) in lung homeostasis is unknown.Objectives: 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.Methods: FSTL-1 hypomorphic (FSTL-1 Hypo) mice underwent lung morphometry, pulmonary function testing, and microcomputed tomography. Fstl1 expression was determined in wildtype 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 in vitro examination. FSTL1 SNP analysis was performed in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort.Measurements and Main Results: FSTL-1 Hypo mice developed spontaneous emphysema, independent of smoke exposure. Fstl1 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 Nr4a1, an orphan nuclear hormone receptor that negatively regulates NF-kB (nuclear factor-kB) signaling. In vitro, recombinant FSTL-1 treatment of macrophages attenuated NF-kB p65 phosphorylation in an Nr4a1-dependent manner. Within the COPDGene cohort, several SNPs in the FSTL1 region corresponded to chronic obstructive pulmonary disease and lung function.Conclusions: 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 Nr4a1. Further study of the mechanisms involving FSTL-1 in lung homeostasis, immune regulation, and NF-kB signaling may provide additional insight into the pathophysiology of emphysema and inflammatory lung diseases.

The Role of the ECM in Lung Cancer Dormancy and Outgrowth

“…Osteopontin interacts directly with α4- and α9β1 integrins to promote tumor cell invasion ( 104 ), with the alternatively spliced C-terminally truncated form of the protein being particularly pro-invasive ( 105 ). Follistatin-like protein 1, which regulates alveolar maturation in the developing lung by inhibiting BMP4/SMAD1/3/5 signaling ( 106 ) and inhibits emphysema development in response to injury ( 107 ) also binds directly to pro-osteopontin to prevent its proteolytic activation and thus inhibit lung cancer metastasis. This likely underpins why the expression of follistatin-like 1 protein is downregulated in NSCLC and low expression of this protein is associated with poor survival ( 101 ).…”

A Novel Role for the Nuclear Receptor, NR4A1, inKlebsiella pneumoniaeLung Infection

“…Given that our work and others indicated Nr4a1 -/macrophages had a dysregulated tolerization phenotype, it was unexpected that Nr4a1 -/macrophages retained K. pneumoniae killing ability (18). Despite genetic profiles noting that Nr4a1 is induced in neutrophils in response to inflammatory stimuli, no prior work has determined what role Nr4a1 has in the neutrophil response, and the finding that Nr4a1 is critically important in neutrophils, and not macrophages, has not been previously reported (30,31).…”

“…While some genes were unchanged, reduced lung expression of the innate pro-inflammatory cytokines, Il1b and Il6, as well as the neutrophil recruitment chemokine, Cxcl2, 5 hours after infection suggested an innate phagocyte response pathway defect (32). Several disease models have shown that macrophage or monocyte expression of NR4A1 has significant impact on inflammation in models of cardiovascular disease, LPS-induced sepsis, and fibrosis (6,7,17,18,33,34). However, in each of these models, NR4A1 modulated macrophage inflammatory genes in response to insult or the deletion of Nr4a1 resulted in an exaggerated macrophage inflammatory phenotype, while we observed reduced pro-inflammatory cytokines in K.…”

“…Specifically, NR4A1 is a factor in macrophage development and inflammatory response through polarization and transcriptional regulation (12)(13)(14)(15)(16). Within macrophages, NR4A1 exhibits a direct effect on the NF-kB pathway by directly blocking p65 from binding to the kB element, and prior work has shown deletion of the Nr4a1 gene increases p65 phosphorylation, thus activating NF-kB mediated transcription, in macrophages (17,18).…”

FSTL1 aggravates Cigarette smoke-induced airway inflammation and airway remodeling by regulating autophagy

“…Moreover, FSTL1 can induce EMT and airway remodeling in asthma 34 . Several FSTL1 SNPs were found corresponded to COPD and lung function, and FSTL-1 de ciency might protect mice from cigarette smoke induced emphysema 35 . In the present study, we further unravel the role of FSTL1 in the pathogenesis of COPD.…”