The role of JAK/STAT signaling in neutrophilic airway inflammation

<bold>Background:</bold> Neutrophilic inflammation is a common feature of chronic inflammatory respiratory diseases like COPD and is associated with corticosteroid resistance. The IL-23/IL-17 axis is recognized for its contribution to Th17-induced neutrophilic airway inflammation. While the involvement of IL-23 and IL-17A in neutrophil recruitment is well-established, their direct impact on neutrophils remains unclear. IL-23 receptors, associated with TYK2 and JAK2 kinases, are also under investigation in this context. Hypothesis: Dysregulation in the JAK/STAT pathway, particularly involving the IL-23/IL-17 axis and TYK2-JAK2 kinase, plays a key role in neutrophilic inflammation in COPD. Targeting this pathway with JAK inhibitors may offer a promising therapeutic intervention alongside standard COPD treatment. <bold>Results:</bold> To study functional aspects, in vitro migration assays were performed on human neutrophils. Isolated neutrophils were pretreated with Brepocitinib, a TYK2-JAK1-JAK2 inhibitor, and further stimulated with IL-17 and IL-23 for migration. IL-17A and IL-23 enhanced neutrophil migration in vitro which was abrogated by the JAK inhibitor Brepocitinib. In an in vivo setting, IL-23 augmented the migration of neutrophils into the airways, which was mitigated by Brepocitinib. The GR α to GR β ratio was observed to be reduced with IL-23, and IL-17 pretreatment, suggesting a decrease in corticosteroid sensitivity. All the above analyses were performed using flow cytometry. <bold>Conclusions:</bold> Our preliminary data indicates the involvement of the IL-23/IL-17 axis in neutrophilic airway inflammation and related corticosteroid resistance, highlighting the potential of JAK inhibitors as an additional therapeutic approach.