GM-CSF contributes to aortic aneurysms resulting from SMAD3 deficiency
Ping Ye, … , Qiulun Lv, Jiahong Xia
Ping Ye, … , Qiulun Lv, Jiahong Xia
Published April 15, 2013
Citation Information: J Clin Invest. 2013;123(5):2317-2331. https://doi.org/10.1172/JCI67356.
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GM-CSF contributes to aortic aneurysms resulting from SMAD3 deficiency

Abstract

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-γ 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-6Chi 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.

Authors

Ping Ye, Wenhao Chen, Jie Wu, Xiaofan Huang, Jun Li, Sihua Wang, Zheng Liu, Guohua Wang, Xiao Yang, Peng Zhang, Qiulun Lv, Jiahong Xia

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Figure 5

Aneurysms occur in the context of chronic inflammation.

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Aneurysms occur in the context of chronic inflammation. (A) Representati...
(A) Representative H&E staining of longitudinal and transverse sections of the ascending aorta from 1-month-old Smad3+/+ and Smad3–/– mouse showing inflammatory cell infiltration in the Smad3–/– aortic root and milder infiltration in that of Smad3+/+ mice. Original magnification, ×100; ×400 (magnified insets). (B) Severity of inflammatory cell infiltration, elastin degradation, and aortic root size in the chimeric mice. The aortic root of Smad3+/+ recipient mouse receiving BM cells from Smad3–/– mouse showed severe inflammatory cell infiltration, elastin degradation, and enlargement of aortic root compared with that of Smad3+/+ recipient mouse receiving BM cells from Smad3+/+ mouse. The aortic root of Smad3–/– mice showed significantly ameliorated pathological changes after receiving Smad3+/+ BM cells. *P < 0.01; **P < 0.001. (C) Representative H&E staining of transverse sections of the aortic root from chimeric mice. Of note, WT recipient mouse receiving BM cells from Smad3–/– mouse revealed a substantially increased accumulation of inflammatory cells within the adventitia and infiltration of inflammatory cells into the media. Original magnification, ×400.