Key roles of CD4+ T cells and IFN-gamma in the development of abdominal aortic aneurysms in a murine model.
Abdominal aortic aneurysm (AAA) is one of a number of diseases associated with a prominent inflammatory cell infiltrate and local destruction of structural matrix macromolecules. This inflammatory infiltrate is predominately composed of T lymphocytes and macrophages. Delineating specific contribution of these inflammatory cells and their cytokines in AAA formation is the key to understanding AAA and other chronic inflammatory disease processes. Our previous studies have demonstrated that macrophages are the major source of matrix metalloproteinase-9, which is required for aneurysmal degeneration in the murine AAA model. However, the role of CD4(+) T cells, the most abundant infiltrates in aneurysmal aortic tissue, is uncertain. In the present study, we found that in the absence of CD4(+) T cells, mice are resistant to aneurysm induction. Previous studies have shown that IFN-gamma levels are increased in AAA. IFN-gamma is a main product of T cells. Intraperitoneal IFN-gamma was able to partially reconstitute aneurysms in CD4(-/-) mice. Furthermore, mice with a targeted deletion of IFN-gamma have attenuation of MMP expression and inhibition of aneurysm development. Aneurysms in IFN-gamma(-/-) mice can be reconstituted by reinfusion of competent splenocytes from the corresponding wild-type mice. This study demonstrates the pivotal role that T cells and the T cell cytokine, IFN-gamma, play in orchestrating matrix remodeling in AAA. This study has important implications for other degenerative diseases associated with matrix destruction.
Xiong
Wanfen
W
Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Zhao
Yong
Y
Prall
Amy
A
Greiner
Timothy C
TC
Baxter
B Timothy
BT
D000818:Animals; D001012:Aorta, Abdominal / Q000166:cytology / Q000201:enzymology; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017710:Lymphocyte Transfusion; D017737:Macrophages, Peritoneal / Q000201:enzymology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000166:cytology / Q000201:enzymology; D011994:Recombinant Proteins / Q000008:administration & dosage; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D011994:Recombinant Proteins; D007371:Interferon-gamma; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9