The IL-23 axis and innate immunity in the airways

Sammanfattning: The Interleukin-23 (IL-23) axis is a communication system that integrates innate and adaptive immunity. When triggered by microbial stimuli, antigen presenting cells can secrete the cytokine IL-23, leading to the production of IL-17 and IL-22. These cytokines facilitate the recruitment of neutrophils that can eliminate microbes, but may also cause epithelial damage through extensive inflammation. At the same time, the IL-23 axis protects the epithelium through the production of antimicrobial peptides. The protective role of the IL-23 axis for local epithelial defence led us to ask whether inflammatory cells of the airway epithelium can produce IL-22, a cytokine associated with the IL-23 axis. We showed that airway macrophages responded to IL-23 and a bacterial stimulus with the secretion of IL-22. This constitutes a local and accessible source of IL-22 during activation of the innate arm of pulmonary host defence. The IL-23 axis leads to neutrophil recruitment which risks damaging epithelial tissue. Therefore, a strict regulation of the production of these cytokines is necessary. We showed that IL-17 exerts a negative feedback effect on IL-23, thus decreasing its own production. Further, the IL-17 receptor was present on macrophages demonstrating a prerequisite to this response. The airway epithelium is protected by antimicrobial peptides functioning as innate antibiotics, several of which are regulated by the IL-23 axis. We demonstrated the expression of two antimicrobial peptides, calprotectin and LL-37, in healthy human airways. Of these, only LL-37 was induced by the gram-negative bacterial stimulus endotoxin in this setting. This demonstrates the involvement of LL-37 in the innate immune response against gramnegative bacteria. Finally, we quantified cytokines associated with the IL-23 axis in smokers with and without chronic obstructive pulmonary disease. Airway IL-17 did not differ significantly between the groups, but plasma IL-22 was increased in smokers, demonstrating a smoking induced systemic effect on the IL-23 axis. Neutrophils in the airways displayed signs of activation and could be further activated by TNFα, indicating that the local microenvironment can affect neutrophil activation.