Interaction Between PKR and ER Stress in the Pathogenesis of Neutrophilc Severe Asthma

The double-stranded RNA (dsRNA)-activated serine/threonine kinase R (PKR) is well characterized as an essential component of the innate antiviral response. In fact, PKR is implicated in TLR signal transduction in response to bacterial cell wall components. Furthermore, PKR activation is associated with IgE class switching and subsequent induction of IgE-mediated disorders such as allergy and asthma. As well known, PKR phosphorylates e-IF2α, one of branches for unfoled protein response (UPR). Conversely, endoplasmic reticulum (ER) stress activates PKR which stimulates various inflammatory signaling pathways. However, its contribution to the asthmatic inflammation and airway hyperresponsiveness, especially steroid-resistant severe asthma has not yet been elucidated. In this study, we investigated whether PKR activation is involved in the pathogenic symptoms of severe asthma and which molecular mechanism is associated with the role of PKR in the pathogenesis of asthma focusing on ER stress. We found that PKR inhibition  using 2-AP decreased severe asthmatic features; the number of airway inflammatory cells in bronchioalveolar lavage (BAL) fluids, airway hyperresponsiveness, and the expression of Th2 cytokines, IL-17 and KC in lung tissues. Interestingly, the PKR expression was increased in lung tissues from mice sensitized with ovalbumin (OVA) and lipopolysaccharide (LPS) and challenged with OVA (OVA_LPS-OVA mice). Moreover, the phosphorylation of PKR and the expression of ER stress marker, CHOP and GRP78 in primary cultured tracheal epithelial cells from mice. This study indicates that PKR activation contributes to the pathogenesis of  the severe neutrophilic asthma through the induction of ER stress in bronchial epithelium, highlighting the therapeutic potential of PKR inhibitor as well as the novel role of PKR as an immune modulator in allergic airway inflammation.