Epithelial signatures in respiratory disease
The epithelium of the human airways protects us against harm and helps maintain immune homeostasis. In respiratory diseases such as asthma and COPD, the functions of the epithelium are altered and can cause or contribute to disease progression. Additionally, these diseases are heterogeneous in regard to which inflammatory mechanisms and pathways are activated, thus creating inflammatory endotypes. Due to these differing endotypes, not all patients respond similarly to currently available treatments. Increased understanding of these endotypes will enable a precision medicine approach for respiratory diseases. In this thesis, responses and functions of the airway epithelium in different possible inflammatory endotypes are investigated using a primary cell-based model system. Three types of epithelial signatures are established in response to inflammatory cytokines: gene expression, extracellular vesicle proteome, and miRNA expression. In Paper I, the IL-6 trans-signaling gene signature is used to identify a subtype of asthma patients with increased activation of this pathway in the airway epithelium. These patients demonstrate increased inflammation, epithelial barrier damage, and higher number of asthma exacerbations indicative of poorly controlled disease. This suggests that these patients could benefit from treatment blocking activation of the IL-6 transsignaling pathway. In Paper II, extracellular vesicles released from epithelial cells stimulated with T2 and Th17 cytokines show proteomic differences related to airway disease-relevant processes. This is exemplified through the effect of the vesicles released under Th17 inflammatory conditions in promoting neutrophil migration. These findings enhance the knowledge about the contribution of epithelial extracellular vesicles in airway disease. In Paper III, Th17 cytokines are shown to cause disruption of the airway epithelial barrier and induce the expression of several miRNAs predicted to target barrier-related genes. Preliminary results identify two miRNAs as possible candidates that interact with, and cause decreased levels of, mRNAs encoding proteins involved in formation of the epithelial barrier. This highlights the role of miRNAs as master regulators of genes important to airway epithelial functions. Altogether, these studies show the diverse and fine-tuned responses and functions of the airway epithelium in inflammatory environments similar to what could be present in patients with respiratory disease. The results thus contribute to the understanding of endotype-specific processes taking place locally in the airways. Ultimately, increased knowledge of disease-driving mechanisms will lead to the development of novel treatments and biomarkers that can be used to improve the lives of patients with respiratory disease.
Parts of work
I. Jevnikar, Z., Östling, J., Ax, E., Calvén, J., Thörn, K., Israelsson, E., Öberg, L., Singhania, A., Lau, L.C.K., Wilson, S..J, Ward, J.A., Chauhan, A., Sousa, A.R., De Meulder, B., Loza, M.J., Baribaud, F., Sterk, P.J., Chung, K.F., Sun, K., Guo, Y., Adcock, I.M., Payne, D., Dahlén, B., Chanez, P., Shaw, D.E., Krug, N., Hohlfeld, J.M., Sandström, T., Djukanovic, R., James, A., Hinks, T.S.C., Howarth, P.H., Vaarala, O., van Geest, M. & Olsson, H.; Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes study group. (2019). Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation. Journal of Allergy and Clinical Immunology, 143(2), 577-590. ::doi::10.1016/j.jaci.2018.05.026II. Ax, E., Jevnikar, Z., Cvjetkovic, A., Malmhäll, C., Olsson, H., Rådinger, M. & Lässer, C. (2020). T2 and T17 cytokines alter the cargo and function of airway epithelium-derived extracellular vesicles. Respiratory Research, 21:155. ::doi::10.1186/s12931-020-01402-3III. Ax, E., Weidner, J., Winslow, S., Lässer, C., Jevnikar, Z., Olsson, H. & Rådinger, M., Th17 cytokines mediate airway epithelial barrier dysfunction – A possible role for miRNAs. In manuscript.
Doctor of Philosophy (Medicine)
University of Gothenburg. Sahlgrenska Academy
Inst of Medicine. Department of Internal Medicine and Clinical Nutrition
Torsdagen den 16 december 2021, kl. 9.00, Hörsal Europa, Konferenscentrum Wallenberg, Medicinaregatan 20, Göteborg
Date of defence