The IL-23 axis and innate immunity in the airways
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.
Parts of work
I. Hansson M, Silverpil E, Lindén A, Glader P. Interleukin-22 produced by alveolar macrophages during activation of the innate immune response. Inflammation Research 2013. Jun;62(6):561-9. ::PMID::23474919II. Silverpil E, Wright AK, Hansson M, Jirholt P, Henningsson L, Smith ME, Gordon SB, Iwakura Y, Gjertsson I, Glader P, Lindén A. Negative feedback on IL-23 exerted by IL-17A during pulmonary inflammation. Innate Immunity 2013 Oct; 19(5):479-92. ::PMID::23295184III. Smith ME*, Stockfelt M*, Tengvall S, Bergman P, Lindén A, Qvarfordt I. Endotoxin Exposure Increases LL-37 – but Not Calprotectin – in Healthy Human Airways. Journal of Innate Immunity. 2017. *Joint first authorship. ::PMID::28605742IV. Stockfelt M, Christenson K, Andersson A, Björkman L, Padra M, Sun J, Levänen B, Ganguly K, Asgeirsdottir H, Qvarfordt I, Bylund J and Lindén A. Neutrophil activation and associated cytokines before and after extravasation into the airways of smokers with and without COPD. Manuscript in preparation.
Doctor of Philosophy (Medicine)
University of Gothenburg. Sahlgrenska Academy
Inst of Medicine. Department of Internal Medicine and Clinical Nutrition
Fredagen den 1 december 2017, kl 9.00, Föreläsningssalen våning 3, Guldhedsgatan 10A, Göteborg
Date of defence