Blockade of interleukin-2-inducible T-cell kinase signaling attenuates acute lung injury in mice through adjustment of pulmonary Th17/Treg immune responses and reduction of oxidative stress

Abstract

Acute lung injury (ALI) is linked with considerable morbidity and mortality. ALI can be caused by various agents, one of them being sepsis. ALI is characterized by injury to vascular endothelium and alveolar epithelium that results in edema, pulmonary immune cells infiltration and hypoxemia. Neutrophils and T cells particularly play a huge role in amplification of pulmonary inflammation through release of multiple inflammatory mediators. Recent reports suggest a strong involvement of Th17 cells and oxidative stress in initiation/amplification of pulmonary inflammation during ALI. Interleukin-2-inducible T-cell kinase (ITK) plays a key role in Th17 cell development through control of several transcription factors. Therefore, our study explored the role of ITK on airway inflammation (total/neutrophilic cell counts, myeloperoxidase activity, E-cadherin expression, histopathological analyses) and effect of its inhibition on various inflammatory/anti-inflammatory pathways during ALI [phosphorylated-ITK (p-ITK), NFATc1, IL-17A, STAT3, Foxp3, IL-10, iNOS, nitrotyrosine, lipid peroxides). ALI was associated with increased total/neutrophilic cell counts and myeloperoxidase activity, and decreased E-cadherin expression in airway epithelial cells (AECs) which was concurrent with upregulation of p-ITK, NFATc1, IL-17A, STAT3 in CD4+ T cells and iNOS/nitrotyrosine in AECs. Treatment with ITK inhibitor reversed ALI-induced changes in airway inflammation and Th17 cells/oxidative stress. Treatment with ITK inhibitor further expanded Treg cells in mice with ALI. In short, our study proposes that ITK signaling plays a significant role in sepsis-induced ALI through upregulation of Th17 cells and oxidative stress. Further, findings provide evidence that ITK blockade could be a potential treatment strategy to attenuate airway inflammation associated with ALI.