title: 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.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ye
authors.forename: Wenhao
authors.initials: W
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Huang
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Sihua
authors.initials: S
authors.lastname: Wang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.forename: Guohua
authors.initials: G
authors.lastname: Wang
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Qiulun
authors.initials: Q
authors.lastname: Lv
authors.forename: Jiahong
authors.initials: J
authors.lastname: Xia
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001014:Aortic Aneurysm / Q000378:metabolism*; D039481:CD11b Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D003433:Crosses, Genetic; D004452:Echocardiography; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D051900:Smad3 Protein / Q000172:deficiency* / Q000378:metabolism*
chemical_list: D039481:CD11b Antigen; D020381:Interleukin-17; D051900:Smad3 Protein; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor