Attenuation of Myeloid Specific TGFβ Signaling Induces Inflammatory Cerebrovascular Disease and Stroke
Rationale: Cryptogenic strokes, those of unknown cause, have been estimated as high as 30-40% of strokes. Inflammation has been suggested as a critical etiological factor. However, there is lack of experimental evidence.
Objective: In this study, we investigated inflammation associated stroke etiology using a mouse model that developed spontaneous stroke due to myeloid deficiency of TGFβ signaling.
Methods and Results: We report that mice with deletion of Tgfbr2 in myeloid cells (Tgfbr2Myeko) 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 Tgfbr2Myeko bone marrow transplant, and can be rescued in Tgfbr2Myeko mice with wild-type bone marrow. The underlying mechanisms involved an increased type 1 inflammation, and cerebral endotheliopathy, characterized by elevated NFΚB activation and TNF 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 TGFβ signaling in myeloid cells is required for maintenance of vascular health, and provide insight into inflammation-mediated cerebrovascular disease and stroke.
- Received November 28, 2016.
- Revision received October 12, 2017.
- Accepted October 18, 2017.