Rationale: Cryptogenic strokes, those of unknown cause, have been estimated as high as 30% to 40% of strokes. Inflammation has been suggested as a critical etiologic factor. However, there is lack of experimental evidence.

Objective: In this study, we investigated inflammation-associated stroke using a mouse model that developed spontaneous stroke because of myeloid deficiency of TGF-β (transforming growth factor-β) signaling.

Methods and Results: We report that mice with deletion of Tgfbr2 in myeloid cells (Tgfbr2^Myeko) developed cerebrovascular inflammation in the absence of significant pathology in other tissues, culminating in stroke and severe neurological deficits with 100% penetrance. The stroke phenotype can be transferred to syngeneic wild-type mice via Tgfbr2^Myeko bone marrow transplant and can be rescued in Tgfbr2^Myeko mice with wild-type bone marrow. The underlying mechanisms involved an increased type 1 inflammation and cerebral endotheliopathy, characterized by elevated NF-κB (nuclear factor-κB) activation and TNF (tumor necrosis factor) production by myeloid cells. A high-fat diet accelerated stroke incidence. Anti-TNF treatment, as well as metformin and methotrexate, which are associated with decreased stroke risk in population studies, delayed stroke occurrence.

Conclusions: Our studies show that TGF-β signaling in myeloid cells is required for maintenance of vascular health and provide insight into inflammation-mediated cerebrovascular disease and stroke.

中文翻译：

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髓系特异性 TGFβ 信号通路的减弱会导致炎症性脑血管疾病和中风新奇和意义

理由：据估计，原因不明的隐源性中风占中风的 30% 至 40%。炎症被认为是一个关键的病因。但是，缺乏实验证据。

目的：在这项研究中，我们使用小鼠模型研究了炎症相关的中风，该模型由于 TGF-β（转化生长因子-β）信号转导的骨髓缺乏而发展为自发性中风。

方法和结果：我们报告说，骨髓细胞中Tgfbr2缺失的小鼠 ( Tgfbr2 ^Myeko ) 在其他组织没有明显病理改变的情况下发展为脑血管炎症，最终导致中风和严重的神经功能缺损，外显率为 100%。中风表型可通过Tgfbr2 ^Myeko骨髓移植转移至同基因野生型小鼠，^{并可在 Tgfbr2 Myeko中挽救}具有野生型骨髓的小鼠。潜在机制涉及增加的 1 型炎症和脑内皮病，其特征是骨髓细胞产生的 NF-κB（核因子-κB）活化和 TNF（肿瘤坏死因子）升高。高脂肪饮食加速中风发病率。在人群研究中，抗 TNF 治疗以及二甲双胍和甲氨蝶呤与降低中风风险相关，延缓了中风的发生。

结论：我们的研究表明，骨髓细胞中的 TGF-β 信号传导是维持血管健康所必需的，并有助于深入了解炎症介导的脑血管疾病和中风。