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

• Published in: Circulation research 2017-12, Vol.121 (12), p.1360-1369
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Bone marrow; Bone marrow transplantation; Cell Line; Clonal deletion; High fat diet; Immunosuppressive Agents - therapeutic use; Inflammation; Inflammation - complications; Inflammation - metabolism; Metformin; Metformin - therapeutic use; Methotrexate; Methotrexate - therapeutic use; Mice; Mice, Inbred C57BL; Myeloid cells; Myeloid Cells - metabolism; Neurological diseases; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Penetrance; Phenotypes; Population studies; Rodents; Signal Transduction; Stroke; Stroke - etiology; Stroke - genetics; Stroke - metabolism; Stroke - prevention & control; Syngeneic grafts; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Tumor necrosis factor; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.116.310349

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. 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. 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 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. 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.