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IL-17A expressed on neutrophil extracellular traps promotes mesenchymal stem cell differentiation toward bone-forming cells in ankylosing spondylitis |
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| Authors: | Charalampos Papagoras Akrivi Chrysanthopoulou Alexandros Mitsios Maria Ntinopoulou Victoria Tsironidou Aristea K Batsali Helen A Papadaki Panagiotis Skendros Konstantinos Ritis |
| Institution: | 1. First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece;2. Laboratory of Molecular Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
Charalampos Papagoras and Akrivi Chrysanthopoulou should be considered as joint first author.;3. Laboratory of Molecular Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece;4. Haemopoiesis Research Laboratory, School of Medicine, University of Crete, Heraklion, Greece;5. Haemopoiesis Research Laboratory, School of Medicine, University of Crete, Heraklion, Greece Department of Hematology, School of Medicine, University of Crete, Heraklion, Greece |
| Abstract: | Ankylosing spondylitis (AS) is an inflammatory disease characterized by excessive bone formation. We investigated the presence of neutrophil extracellular traps (NETs) in AS and how they are involved in the osteogenic capacity of bone marrow mesenchymal stem cells (MSCs) through interleukin-17A (IL-17A). Peripheral neutrophils and sera were obtained from patients with active AS and healthy controls. NET formation and neutrophil/NET-associated proteins were studied using immunofluorescence, immunoblotting, qPCR, and ELISA. In vitro co-culture systems of AS NET structures and MSCs isolated from controls were deployed to examine the role of NETs in the differentiation of MSCs toward osteogenic cells. Analysis was performed using specific staining and qPCR. Neutrophils from patients with AS were characterized by enhanced formation of NETs carrying bioactive IL-17A and IL-1β. IL-17A-enriched AS NETs mediated the differentiation of MSCs toward bone-forming cells. The neutrophil expression of IL-17A was positively regulated by IL-1β. Blocking IL-1β signaling on neutrophils with anakinra or dismantling NETs using DNase-I disrupted osteogenesis driven by IL-17A-bearing NETs. These findings propose a novel role of neutrophils in AS-related inflammation, linking IL-17A-decorated NETs with the differentiation of MSCs toward bone-forming cells. Moreover, IL-1β triggers the expression of IL-17A on NETs offering an additional therapeutic target in AS. |
| Keywords: | Ankylosing spondylitis Interleukin-17 Interleukin-1β Mesenchymal stem cells Neutrophil extracellular traps |