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

Jolly, Lisa; Stavrou, Anastasios; Vanderstoken, Gilles; Meliopoulos, Victoria A.; Habgood, Anthony; Tatler, Amanda L.; Porte, Joanne; Knox, Alan J.; Weinreb, Paul H.; Violette, Shelia M.; Hussell, Tracy; Kolb, Martin; Stämpfli, Martin R.; Schultz‐Cherry, Stacey; Jenkins, Gisli

doi:10.1074/jbc.m114.582262

Cited by 53 publications

(55 citation statements)

References 68 publications

(44 reference statements)

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“…36 Further, influenza was shown to induce transforming growth factor (TGF)-b activation, a known profibrotic mediator, via Tlr3-dependent avb6 integrin. 37 Similarly, our data show increased TGF-b1 and TGF-b3 expression after influenza challenge. These data suggest that primary influenza infection may prime the lung for greater responses to fibrotic stimuli.…”

Section: Discussionsupporting

confidence: 77%

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

Pociask

Robinson

Chen

et al. 2017

The American Journal of Pathology

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Seasonal and pandemic influenza is a cause of morbidity and mortality worldwide. Most people infected with influenza virus display mild-to-moderate disease phenotypes and recover within a few weeks. Influenza is known to cause persistent alveolitis in animal models; however, little is known about the molecular pathways involved in this phenotype. We challenged C57BL/6 mice with influenza A/PR/8/34 and examined lung pathologic processes and inflammation, as well as transcriptomic and epigenetic changes at 21 to 60 days after infection. Influenza induced persistent parenchymal lung inflammation, alveolar epithelial metaplasia, and epithelial endoplasmic reticulum stress that were evident after the clearance of virus and resolution of morbidity. Influenza infection induced robust changes in the lung transcriptome, including a significant impact on inflammatory and extracellular matrix protein expression. Despite the robust changes in lung gene expression, preceding influenza (21 days) did not exacerbate secondary Staphylococcus aureus infection. Finally, we examined the impact of influenza on miRNA expression in the lung and found an increase in miR-155. miR-155 knockout mice recovered from influenza infection faster than controls and had decreased lung inflammation and endoplasmic reticulum stress. These data illuminate the dynamic molecular changes in the lung in the weeks after influenza infection and characterize the repair process, identifying a novel role for miR-155. (Am J Pathol 2017, 187: 851e863; http://dx

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Section: Discussionsupporting

confidence: 77%

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

Pociask

Robinson

Chen

et al. 2017

The American Journal of Pathology

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“…104 In fact, pulmonary infection with H1N1 virus can result in the activation of SMAD2/3 and also can increase toll like receptor 3 (TLR3) stimulation, which in turn enhances RhoA activity, a novel mechanism contributing to αvβ6 integrin-mediated TGF-β activation, resulting in enhanced epithelial apoptosis, collagen deposition, and then pulmonary fibrosis (Figure 9). 104 In addition, both influenza virus…”

Section: Ie2mentioning

confidence: 99%

Viruses as key modulators of the TGF‐β pathway; a double‐edged sword involved in cancer

Mirzaei

Faghihloo

2018

Reviews in Medical Virology

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Transforming growth factor-β (TGF-β) signaling pathway is a key network in cell signaling that controls vital processes such as proliferation, differentiation, apoptosis, epithelial-mesenchymal transition, and migration, thus acting as a double-edged sword in normal development and diseases, in particular organ fibrosis, vascular disorders, and cancer. Early in tumorigenesis, the pathway exerts anti-tumor effects through suppressing cell cycle and inducing apoptosis, while during late stages, it functions as a tumor promoter by enhancing tumor invasiveness and metastasis. This signaling pathway can be perturbed by environmental and genetic factors such as microbial interference and mutation, respectively. In this way, the present review describes the modulation of the TGF-β pathway by oncogenic human viral pathogens and other viruses. The main mechanisms by which viruses interferes with TGF-β signaling seems to be through (1) the alteration of either TGF-β protein expression or activation, (2) the modulation of the TGF-β receptors or SMADs factors (by interfering with their levels and functions), (3) the alteration of none-SMAD pathways, and (4) indirect interaction with the pathway by the modulation of transcriptional co-activator/repressor and regulators of the pathway. Given the axial role of this pathway in tumorigenesis, it can be regarded as an attractive target for cancer therapy. Hence, further investigations on this subject may represent molecular targets among either TGF-β signaling molecules or viral factors for the treatment and management of viral infection consequences such as cancer.

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“…Upon viral infection, airway epithelial cells produce an array of pro- and anti-inflammatory cytokines and chemokines including the type-I and -III interferons (IFN-α/β and IFN-λ), TNFα, IL-4, IL-8, IL-13, IL-17, CCL3 and RANTES [37], some of which have been shown to interfere with GC action in epithelial cells: TNFα inhibits GC transactivation in A549 cells and BEAS-2B cells [38]; IL-17 induces GC insensitivity in the human bronchial epithelial cell line, 16HBE14o- [39]; and, IFN-λ-induced JAK/STAT signaling activation is insensitive to GC action in A549 cells and air-liquid interface (ALI) differentiated primary human bronchial epithelial cells (HBECs) [40]. Viral infection of airway epithelial cells with RSV [41], RV [42, 43], or IAV [44, 45] also results in increased expression, secretion, and activity of the pleiotropic growth factor transforming growth factor-β (TGF-β). Moreover, endogenous TGF-β enhances RSV replication by induction of cell cycle arrest in an autocrine manner [41], and increases RV replication by suppression of type I/III IFN expression [42, 43].…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-β Activity

et al. 2017

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Asthma and chronic obstructive pulmonary disease (COPD) exacerbations are commonly associated with respiratory syncytial virus (RSV), rhinovirus (RV) and influenza A virus (IAV) infection. The ensuing airway inflammation is resistant to the anti-inflammatory actions of glucocorticoids (GCs). Viral infection elicits transforming growth factor-β (TGF-β) activity, a growth factor we have previously shown to impair GC action in human airway epithelial cells through the activation of activin-like kinase 5 (ALK5), the type 1 receptor of TGF-β. In the current study, we examine the contribution of TGF-β activity to the GC-resistance caused by viral infection. We demonstrate that viral infection of human bronchial epithelial cells with RSV, RV or IAV impairs GC anti-inflammatory action. Poly(I:C), a synthetic analog of double-stranded RNA, also impairs GC activity. Both viral infection and poly(I:C) increase TGF-β expression and activity. Importantly, the GC impairment was attenuated by the selective ALK5 (TGFβRI) inhibitor, SB431542 and prevented by the therapeutic agent, tranilast, which reduced TGF-β activity associated with viral infection. This study shows for the first time that viral-induced glucocorticoid-insensitivity is partially mediated by activation of endogenous TGF-β.

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

Cited by 53 publications

References 68 publications

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

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

Viruses as key modulators of the TGF‐β pathway; a double‐edged sword involved in cancer

Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-β Activity

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