TGF-β1 affects endothelial cell interaction with macrophages and T cells leading to the development of cerebrovascular amyloidosis.
Astrocyte-endothelial cell (EC) interactions play a major role in the function of the neurovascular unit. Dysfunction in these interactions may lead to amyloid accumulation in blood vessels and may cause microhemorrhage and cognitive impairment. Transforming growth factor-β1 (TGF-β1) expression levels positively correlate with the degree of cerebrovascular amyloid in Alzheimer's disease (AD) cases. Furthermore, expression of TGF-β1 driven by the GFAP promoter in mice leads to an age-related deposition of amyloid, such as β-amyloid (Aβ), around cerebral blood vessels. Here, we demonstrate that TGF-β1 affects the cross talk between EC and inflammation, leading to a reduction in macrophage activity as measured by protein levels and migration ability. Changes in EC secreted factors following TGF-β1 stimulation also affect CD4(+) T cell activation, as shown by a reduction in the levels of IFN-γ. Moreover, while medium from EC can stimulate macrophages to clear insoluble cerebrovascular amyloid from an AD mouse brain, pre-incubation of EC with TGF-β1 reduces the ability of EC to affect macrophage activity. Our findings support the importance of cross talk between EC, macrophages and CD4(+) T cells in preventing cerebrovascular amyloid deposition. Understanding EC-immune system interactions may pave the way to new therapeutic approaches for cerebrovascular amyloidosis diseases.
Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Ronen
R
Weiss
Veronica
V
Lifshitz
Dan
D
Frenkel
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism* / Q000503:physiopathology; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D016207:Cytokines / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
D016207:Cytokines; D053773:Transforming Growth Factor beta1