Augmentative effects of leukemia inhibitory factor reveal a critical role for TYK2 signaling in vascular calcification

被引:1
作者
Alesutan, Ioana [1 ]
Razazian, Mehdi [1 ]
Luong, Trang T. D. [1 ]
Estepa, Misael [2 ,3 ,4 ]
Pitigala, Lakmi [1 ]
Henze, Laura A. [2 ,3 ,4 ]
Obereigner, Jakob [1 ]
Mitter, Gregor [1 ]
Zickler, Daniel [3 ,4 ,5 ]
Schuchardt, Mirjam [3 ,4 ,5 ,6 ]
Deisl, Christine [1 ]
Makridakis, Manousos [7 ]
Gollmann-Tepekoeylue, Can [6 ]
Pasch, Andreas [1 ,9 ]
Cejka, Daniel [10 ]
Suessner, Susanne [11 ]
Antlanger, Marlies [1 ,12 ,13 ]
Bielesz, Bernhard [1 ,14 ]
Mueller, Mathias [15 ]
Vlahou, Antonia [7 ]
Holfeld, Johannes [8 ]
Eckardt, Kai-Uwe [3 ,4 ,5 ]
Voelkl, Jakob [1 ,3 ,4 ,5 ,16 ]
机构
[1] Johannes Kepler Univ Linz, Inst Physiol & Pathophysiol, Krankenhausstr 5, A-4020 Linz, Austria
[2] Dept Internal Med & Cardiol, Berlin, Germany
[3] Free Univ Berlin, Berlin, Germany
[4] Humboldt Univ, Berlin, Germany
[5] Charite Univ Med Berlin, Dept Nephrol & Med Intens Care, Berlin, Germany
[6] Med Sch Berlin, Fac Med, Berlin, Germany
[7] Biomed Res Fdn Acad Athens, Ctr Syst Biol, Athens, Greece
[8] Med Univ Innsbruck, Dept Cardiac Surg, Innsbruck, Austria
[9] Calciscon AG, Biel, Switzerland
[10] Ordensklinikum Linz, Internal Med Nephrol 3, Transplantat Med, Rheumatol, Linz, Austria
[11] Red Cross Transfus Serv Upper Austria, Linz, Austria
[12] Kepler Univ Hosp, Dept Internal Med 2, Linz, Austria
[13] Johannes Kepler Univ Linz, Linz, Austria
[14] Med Univ Vienna, Dept Med 3, Div Nephrol & Dialysis, Vienna, Austria
[15] Univ Vet Med Vienna, Inst Anim Breeding & Genet, Vienna, Austria
[16] DZHK German Ctr Cardiovasc Res, Partner Site Berlin, Berlin, Germany
基金
奥地利科学基金会;
关键词
chronic kidney disease; leukemia inhibitory factor; STAT3; TYK2; vascular calcification; vascular smooth muscle cells; JAK/STAT PATHWAY; FACTOR LIF; CYTOKINE; RECEPTOR; CELLS; ACTIVATION; UROKINASE; DIFFERENTIATION; PROGRESSION; EXPRESSION;
D O I
10.1016/j.kint.2024.07.011
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:611 / 624
页数:14
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