CRISPLD2 (LGL1) inhibits proinflammatory mediators in human fetal, adult, and COPD lung fibroblasts and epithelial cells

Abstract

Abstract Chronic lung disease of prematurity/bronchopulmonary dysplasia (BPD) is the leading cause of perinatal morbidity in developed countries. Inflammation is a prominent finding. Currently available interventions have associated toxicities and limited efficacy. While BPD often resolves in childhood, survivors of preterm birth are at risk for acquired respiratory disease in early life and are more likely to develop chronic obstructive pulmonary disease (COPD) in adulthood. We previously cloned Crispld2 (Lgl1), a glucocorticoid‐regulated mesenchymal secretory protein that modulates lung branching and alveogenesis through mesenchymal–epithelial interactions. Absence of Crispld2 is embryonic lethal. Heterozygous Crispld2+/− mice display features of BPD, including distal airspace enlargement, disruption of elastin, and neonatal lung inflammation. CRISPLD2 also plays a role in human fetal lung fibroblast cell expansion, migration, and mesenchymal–epithelial signaling. This study assessed the effects of endogenous and exogenous CRISPLD2 on expression of proinflammatory mediators in human fetal and adult (normal and COPD) lung fibroblasts and epithelial cells. CRISPLD2 expression was upregulated in a lipopolysaccharide (LPS)‐induced human fetal lung fibroblast line (MRC5). LPS‐induced upregulation of the proinflammatory cytokines IL‐8 and CCL2 was exacerbated in MRC5‐CRISPLD2 knockdown cells. siRNA suppression of endogenous CRISPLD2 in adult lung fibroblasts (HLFs) led to augmented expression of IL‐8, IL‐6, CCL2. LPS‐stimulated expression of proinflammatory mediators by human lung epithelial HAEo‐ cells was attenuated by purified secretory CRISPLD2. RNA sequencing results from HLF‐CRISPLD2 knockdown suggest roles for CRISPLD2 in extracellular matrix and in inflammation. Our data suggest that suppression of CRISPLD2 increases the risk of lung inflammation in early life and adulthood.