X-Box–Binding Protein 1 and Innate Immune Responses of Human Cystic Fibrosis Alveolar Macrophages
Year: 2015
Type: article
Abstract: RATIONALE: Alveolar macrophages (AMs) play a key role in host defense to inhaled bacterial pathogens, in part by secreting inflammatory mediators. Cystic fibrosis (CF) airways exhibit a persistent, robust inflammatory response that may contribute to the pathophysiology of CF. Recent findings have linked endoplasmic reticulum stress responses mediated by inositol-requiring enzyme 1α-dependent messenger RNA splicing (activation) of X-box-binding protein-1 (XBP-1s) to inflammation in peripheral macrophages. However, the role of XBP-1s in CF AM function is not known. OBJECTIVES: To evaluate inflammatory responses of AMs from chronically infected/inflamed human CF lungs and test whether XBP-1s is required for AM-mediated inflammation. METHODS: Basal and LPS-induced inflammatory responses were evaluated in primary cultures of non-CF versus CF AMs. XBP-1s was measured and its function was evaluated in AMs using 8-formyl-7-hydroxy-4-methylcoumarin (4μ8C), an inhibitor of inositol-requiring enzyme 1α-dependent XBP-1s, and in THP-1 cells stably expressing XBP-1 shRNA, XBP-1s, or a dominant-negative XBP-1. MEASUREMENTS AND MAIN RESULTS: CF AMs exhibited exaggerated basal and LPS-induced production of tumor necrosis factor-α and IL-6, and these responses were coupled to increased levels of XBP-1s. In non-CF and CF AMs, LPS-induced cytokine production was blunted by 4µ8C. A role for XBP-1s in AM inflammatory responses was further established by data from dTHP-1 cells indicating that expression of XBP-1 shRNA reduced XBP-1s levels and LPS-induced inflammatory responses; and LPS-induced inflammation was up-regulated by expression of XBP-1s and inhibited by dominant-negative XBP-1. CONCLUSIONS: These findings suggest that AMs contribute to the robust inflammation of CF airways via an up-regulation of XBP-1s-mediated cytokine production.
Institution: University of North Carolina at Chapel Hill
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
Funders: Cystic Fibrosis Foundation, Wallonie-Bruxelles International, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Center for Gastrointestinal Biology and Disease, School of Medicine, University of North Carolina at Chapel Hill
OpenAlex ID: W1702374914