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. 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.

中文翻译：

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白血病抑制因子的增强作用揭示了 TYK2 信号在血管钙化中的关键作用


慢性肾脏病（CKD）中的内侧血管钙化涉及高磷血症诱导的促炎途径。几种白细胞介素 6 家族成员与血管平滑肌细胞 (VSMC) 的促钙化作用相关，被认为是治疗靶点。因此，我们研究了白血病抑制因子（LIF）在VSMC钙化过程中的作用。发现 VSMC 暴露于磷酸盐后 LIF 表达增加。补充 LIF 会加重病情，而内源性 LIF 或 LIF 受体 (LIFR) 的沉默则改善了 VSMC 中磷酸盐的促钙化作用。可溶性 LIFR 介导对 LIF 的拮抗作用并减少 VSMC 钙化。从机制上讲，LIF 诱导 VSMC 中非受体酪氨酸蛋白激酶 2 (TYK2) 以及信号转导子和转录激活子 3 (STAT3) 的磷酸化。 deucravacitinib（一种用于治疗银屑病的选择性变构口服免疫抑制剂）对 TYK2 的抑制不仅削弱了 LIF 的作用，而且还干扰了磷酸盐诱导的促钙化作用。相反，TYK2过表达会加剧VSMC钙化。 Tyk2 药理学抑制和遗传缺陷可改善小鼠主动脉环的钙化。 Tyk2 抑制和 Tyk2 缺陷小鼠中胆钙化醇诱导的小鼠血管钙化得到改善。同样，在腺嘌呤/高磷诱导的 CKD 后，Abcc6/Tyk2 缺陷小鼠的钙化得到改善。因此，我们的观察表明 LIF 在 CKD 相关血管钙化中发挥作用。因此，LIF 的作用确定了 TYK2 信号传导的核心促钙化作用，这可能是减轻 CKD 血管钙化负担的未来目标。