Abstract
Exposure to respiratory pathogens is a leading cause of exacerbations of airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Pellino-1 is an E3 ubiquitin ligase known to regulate virally-induced inflammation. We wished to determine the role of Pellino-1 in the host response to respiratory viruses in health and disease. Pellino-1 expression was examined in bronchial sections from patients with GOLD stage two COPD and healthy controls. Primary bronchial epithelial cells (PBECs) in which Pellino-1 expression had been knocked down were extracellularly challenged with the TLR3 agonist poly(I:C). C57BL/6 Peli1−/− mice and wild type littermates were subjected to intranasal infection with clinically-relevant respiratory viruses: rhinovirus (RV1B) and influenza A. We found that Pellino-1 is expressed in the airways of normal subjects and those with COPD, and that Pellino-1 regulates TLR3 signaling and responses to airways viruses. In particular we observed that knockout of Pellino-1 in the murine lung resulted in increased production of proinflammatory cytokines IL-6 and TNFα upon viral infection, accompanied by enhanced recruitment of immune cells to the airways, without any change in viral replication. Pellino-1 therefore regulates inflammatory airway responses without altering replication of respiratory viruses.
Highlights
Exacerbations of airways diseases remain a major challenge for respiratory medicine
We previously showed that Pellino-1 knockdown in human airway epithelial cells reduced inflammatory responses to rhinoviral infection, without altering rhinoviral replication (Bennett et al, 2012), and a similar decrease in proinflammatory cytokines has been observed upon Pellino-1 silencing in human myometrial cells after TNF and TLR stimulation (Lim et al, 2018)
We have previously shown that Pellino-2 is not expressed in the human airway epithelium (Bennett et al, 2012), specific staining to Pellino-1 was observed in the airway epithelial cells
Summary
Exacerbations of airways diseases remain a major challenge for respiratory medicine. Viruses are major causes of acute exacerbations in both asthma and COPD, with human rhinovirus being the most commonly associated virus (Sethi and Murphy, 2008; Leigh and Proud, 2015), and influenza A associated with more serious COPD exacerbations requiring hospitalization (Sethi and Murphy, 2008).Pellino-1 Regulates Responses to VirusesNew molecular targets of virus-induced inflammation would have enormous therapeutic potential by reducing excessive and inappropriate inflammation without preventing host defense functions. Based on previous work from our group (Bennett et al, 2012), we examined the role of Pellino-1 in the control of viral-induced airway inflammation. We previously showed that Pellino-1 knockdown in human airway epithelial cells reduced inflammatory responses to rhinoviral infection, without altering rhinoviral replication (Bennett et al, 2012), and a similar decrease in proinflammatory cytokines has been observed upon Pellino-1 silencing in human myometrial cells after TNF and TLR stimulation (Lim et al, 2018). Other studies showed additional roles for Pellino-1 in limiting development of autoimmunity; aged Pellino-1-deficient mice develop an autoimmune phenotype with excess T cell activation compared to aged wild type mice (Chang et al, 2011). Pellino-1 expression may be increased in asthma and COPD (Baines et al, 2011, 2013)
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