Abstract
The stimulator of interferon genes (STING) is a key adaptor protein mediating innate immune defense against DNA viruses. To investigate the role of STING in acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), we isolated primary peripheral blood mononuclear cells (PBMCs) from patients and healthy controls (HCs). Raw264.7 and A549 cells were infected with herpes simplex virus type 1 (HSV-1). Mice with bleomycin-induced lung fibrosis were infected with HSV-1 to stimulate acute exacerbation of the lung fibrosis. Global gene expression profiling revealed a substantial downregulation of interferon-regulated genes (downstream of STING) in the AE-IPF group compared with the HC and stable IPF groups. The PBMCs of the AE-IPF group showed significantly reduced STING protein levels, increased levels of endoplasmic reticulum (ER) stress markers, and elevated apoptosis. HSV-1 infection decreased STING expression and stimulated the ER stress pathways in Raw264.7 and A549 cells in a time- and dose-dependent manner. HSV-1 infection exacerbated the bleomycin-induced lung injury in mice. In the primary bone marrow-derived macrophages of mice treated with bleomycin and HSV-1, STING protein expression was substantially reduced; ER stress was stimulated. Tauroursodeoxycholic acid, a known inhibitor of ER stress, partially reversed those HSV-1-mediated adverse effects in mice with bleomycin-induced lung injury. STING levels in PBMCs increased after treatment in patients showing improvement but remained at low levels in patients with deterioration. Viral infection may trigger ER stress, resulting in STING deficiency and AE-IPF onset.
Highlights
Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is the leading cause of death in patients with IPF [1, 2]
These findings are consistent with the previous reports, which have found that the annual incidence of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is 5–15% and the short-term mortality of AE-IPF is higher than 50% [27,28,29]
42.3% of patients with AE-IPF had a history of cold before the onset of AE-IPF and herpes simplex virus type 1 (HSV-1) infection exacerbated bleomycin-induced lung fibrosis in mice
Summary
Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is the leading cause of death in patients with IPF [1, 2]. The exact etiology of AE-IPF remains unclear, recent studies suggest that viral infection may contribute to the pathogenesis of AE-IPF [2]. Stimulator of interferon genes (STING), known as MITA or MPYS, is encoded by STING in AE-IPF the TMEM173 gene and plays a key role in viral DNA-sensing pathways by regulating the expression of numerous host defense genes, including type I interferons (IFNs) and pro-inflammatory cytokines [4,5,6,7]. TMEM173 gene mutation has been found in patients with severe pulmonary fibrosis, suggesting that STING may be involved in AE-IPF [8]. The molecular mechanism underlying the role of STING in AE-IPF is unknown
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