Influenza Induces Endoplasmic Reticulum Stress, Caspase-12–Dependent Apoptosis, and c-Jun N-Terminal Kinase–Mediated Transforming Growth Factor–β Release in Lung Epithelial Cells

Abstract

Influenza A virus (IAV) infection is known to induce endoplasmic reticulum (ER) stress, Fas-dependent apoptosis, and TGF-β production in a variety of cells. However, the relationship between these events in murine primary tracheal epithelial cells (MTECS), which are considered one of the primary sites of IAV infection and replication, is unclear. We show that IAV infection induced ER stress marker activating transcription factor-6 and endoplasmic reticulum protein 57-kD (ERp57), but not C/EBP homologous protein (CHOP). In contrast, the ER stress inducer thapsigargin (THP) increased CHOP. IAV infection activated caspases and apoptosis, independently of Fas and caspase-8, in MTECs. Instead, apoptosis was mediated by caspase-12. A decrease in ERp57 attenuated the IAV burden and decreased caspase-12 activation and apoptosis in epithelial cells. TGF-β production was enhanced in IAV-infected MTECs, compared with THP or staurosporine. IAV infection caused the activation of c-Jun N-terminal kinase (JNK). Furthermore, IAV-induced TGF-β production required the presence of JNK1, a finding that suggests a role for JNK1 in IAV-induced epithelial injury and subsequent TGF-β production. These novel findings suggest a potential mechanistic role for a distinct ER stress response induced by IAV, and a profibrogenic/repair response in contrast to other pharmacological inducers of ER stress. These responses may also have a potential role in acute lung injury, fibroproliferative acute respiratory distress syndrome, and the recently identified H1N1 influenza-induced exacerbations of chronic obstructive pulmonary disease (Wedzicha JA. Proc Am Thorac Soc 2004;1:115-120) and idiopathic pulmonary fibrosis (Umeda Y, et al. Int Med 2010;49:2333-2336).

Epigenetic and Transcriptomic Regulation of Lung Repair during Recovery from Influenza Infection

“…26 Our finding that ER stress is present in epithelial cells during recovery from influenza infection is consistent with the finding that DNA damage and apoptotic cells are also persistently increased after infection. 27 It is likely that persistent ER stress contributes to the epithelial metaplasia and honeycombing that is seen through 60 days after infection.…”

Influenza Promotes Collagen Deposition via αvβ6 Integrin-mediated Transforming Growth Factor β Activation

“…Increased TGF␤ activation during influenza infection has consistently been associated with enhanced epithelial cell apoptosis (20,57,58). This is supported in vivo by our data showing increased phosphorylated Smad2 and apoptosis 3 days postinfection, and previous work has found that peak viral titers also occur at this time point (59).…”

Mutant surfactant A2 proteins associated with familial pulmonary fibrosis and lung cancer induce TGF-β1 secretion

“…The modulation of net levels of secreted TGF-β1 by ER stress transducers provides insight into the mechanism by which ER stress induced by chemicals or the expression of other misfolded proteins can potentiate TGF-β-mediated fibrosis. For example, others have shown that tunicamycin augments bleomycin-induced pulmonary fibrosis in mice (10), and influenza viral infection of lung epithelial cells can induce ER stress and JNK-mediated TGF-β expression and secretion (27). Secreted TGF-β1 is capable of activating the autocrine positive feedback loop (28); this loop amplifies the expression of TGF-β1, leading to further TGF-β1 secretion and a vicious cycle of exuberant wound repair.…”