o:3681 Augmentative effects of leukemia inhibitory factor reveal a critical role for TYK2 signaling in vascular calcification en Medial vascular calcification in chronic kidney disease (CKD) involves pro-inflammatory pathways induced by hyperphosphatemia. Several interleukin 6 family members have been associated with pro-calcific effects in vascular smooth muscle cells (VSMCs) and are considered as therapeutic targets. Therefore, we investigated the role of leukemia inhibitory factor (LIF) during VSMC calcification. LIF expression was found to be increased following phosphate exposure of VSMCs. LIF supplementation aggravated, while silencing of endogenous LIF or LIF receptor (LIFR) ameliorated the pro-calcific effects of phosphate in VSMCs. The soluble LIFR mediated antagonistic effects towards LIF and reduced VSMC calcification. Mechanistically, LIF induced phosphorylation of the non-receptor tyrosine-protein kinase 2 (TYK2) and signal transducer and activator of transcription-3 (STAT3) in VSMCs. TYK2 inhibition by deucravacitinib, a selective, allosteric oral immunosuppressant used in psoriasis treatment, not only blunted the effects of LIF, but also interfered with the pro-calcific effects induced by phosphate. Conversely, TYK2 overexpression aggravated VSMC calcification. Ex vivo calcification of mouse aortic rings was ameliorated by Tyk2 pharmacological inhibition and genetic deficiency. Cholecalciferol-induced vascular calcification in mice was improved by Tyk2 inhibition and in the Tyk2-deficient mice. Similarly, calcification was ameliorated in Abcc6/Tyk2-deficient mice after adenine/high phosphorus-induced CKD. Thus, our observations indicate a role for LIF in CKD-associated vascular calcification. Hence, the effects of LIF identify a central pro-calcific role of TYK2 signaling, which may be a future target to reduce the burden of vascular calcification in CKD. Chronic Kidney Disease; Leukemia Inhibitory Factor; STAT3; TYK2; Vascular Calcification; Vascular Smooth Muscle Cells 1552099 10.1016/j.kint.2024.07.011 2024-11-06T13:40:28.301Z 44 yes 46 Ioana Alesutan Johannes Kepler University of Linz Jakob Voelkl Johannes Kepler University of Linz / Charité - Universitätsmedizin Berlin / German Centre for Cardiovascular Research person Kai-Uwe Eckardt Charité - Universitätsmedizin Berlin person Antonia Vlahou Innsbruck Medical University person Mathias Müller University of Veterinary Medicine Vienna person 0000-0002-7879-3552 Bernhard Bielesz Medical University of Vienna person Marlies Antlanger Kepler Universitätsklinikum / Johannes Kepler University of Linz person Susanne Suessner Red Cross Transfusion Service of Upper Austria person Daniel Cejka Ordensklinikum Linz Barmherzige Schwestern person Andreas Pasch Johannes Kepler University of Linz person Can Gollmann-Tepeköylü Innsbruck Medical University person Manousos Makridakis Biomedical Research Foundation of the Academy of Athens person Christine Deisl Johannes Kepler University of Linz person Mirjam Schuchardt Charité - Universitätsmedizin Berlin / MSB Medical School Berlin person Daniel Zickler Charité - Universitätsmedizin Berlin person Gregor Mitter Johannes Kepler University of Linz person Laura A. Henze Johannes Kepler University of Linz person Lakmi Pitigala Johannes Kepler University of Linz person Misael Estepa Charité - Universitätsmedizin Berlin person Mehdi Razazian Johannes Kepler University of Linz person Trang T. D. Luong Johannes Kepler University of Linz person application/pdf 3622038 https://phaidra.vetmeduni.ac.at/o:3681 no yes 16 70 1552253 Kidney International 14 106 4 611 624 Elsevier 2024