Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 123, Issue 5, Pages 2317-2331Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI67356
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Funding
- National Nature Science Foundation of China [81070205, 81130056, 81202335, 81100176, 81102240]
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Heterozygous loss-of-function SMAD3 (Mothers against decapentaplegic homolog 3) mutations lead to aneurysm-osteoarthritis syndrome (AOS). In the present study, we found that mice lacking Smad3 had a vascular phenotype similar to AOS, marked by the progressive development of aneurysms. These aneurysms were associated with various pathological changes in transmural inflammatory cell infiltration. Bone marrow transplants from Smad3(-/-) mice induced aortitis and aortic root dilation in irradiated WT recipient mice. Transplantation of CD4(+) T cells from Smad3(-/-) mice also induced aortitis in Smad3(+/+) recipient mice, while depletion of CD4(+) T cells in Smad3(-/-) mice reduced the infiltration of inflammatory cells in the aortic root. Furthermore, IFN-gamma deficiency increased, while IL-17 deficiency decreased, disease severity in Smad3(+/-) mice. Cytokine secretion was measured using a cytokine quantibody array, and Smad3(-/-) CD4(+) T cells secreted more GM-CSF than Smad3(+/+) CD4(+) T cells. GM-CSF induced CD11b(+)Gr-1(+)Ly-6C(hi) inflammatory monocyte accumulation in the aortic root, but administration of anti-GM-CSF mAb to Smad3(-/-) mice resulted in significantly less inflammation and dilation in the aortic root. We also identified a missense mutation (c.985A>G) in a family of thoracic aortic aneurysms. Intense inflammatory infiltration and GM-CSF expression was observed in aortas specimens of these patients, suggesting that GM-CSF is potentially involved in the development of AOS.
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