Attenuation of Myeloid-Specific TGF beta Signaling Induces Inflammatory Cerebrovascular Disease and Stroke

作者：Hollander M Christine; Latour Lawrence L; Yang Dan; Ishii Hiroki; Xiao Zhiguang; Min Yongfen; Ray Choudhury Abhik; Munasinghe Jeeva; Merchant Anand S; Lin P Charles; Hallenbeck John; Boehm Manfred; Yang Li

来源：Circulation Research, 2017, 121(12): 1360-+.

DOI：10.1161/CIRCRESAHA.116.310349

<jats:sec>
<jats:title>
<jats:underline>Rationale:</jats:underline>
</jats:title>
<jats:p>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.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>
<jats:underline>Objective:</jats:underline>
</jats:title>
<jats:p>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.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>
<jats:underline>Methods and Results:</jats:underline>
</jats:title>
<jats:p>
We report that mice with deletion of
<jats:italic>Tgfbr2</jats:italic>
in myeloid cells (
<jats:italic>Tgfbr2</jats:italic>
<jats:sup>Myeko</jats:sup>
) 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
<jats:italic>Tgfbr2</jats:italic>
<jats:sup>Myeko</jats:sup>
bone marrow transplant and can be rescued in Tgfbr2
<jats:sup>Myeko</jats:sup>
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.
</jats:p>
</jats:sec>
<jats:sec>
<jats:title>
<jats:underline>Conclusions:</jats:underline>
</jats:title>
<jats:p>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.</jats:p>
</jats:sec>

• 出版日期2017-12-8