title: Foxp3+ regulatory T cells play a protective role in angiotensin II-induced aortic aneurysm formation in mice.
abstract: Although regulatory T cells (Tregs) have been shown to play a protective role in abdominal aortic aneurysm (AAA) formation, it remains unclear whether expansion of endogenous Foxp3(+) Tregs prevents AAA. In the current study, we determined the effects of endogenous Foxp3(+) Treg expansion or depletion in an experimental model of AAA. We continuously infused 12-week-old apolipoprotein E-deficient mice fed a high-cholesterol diet with angiotensin II (n=60) or normal saline (n=12) by implanting osmotic mini-pumps and evaluated AAA formation at 16 weeks. The angiotensin II-infused mice received interleukin-2/anti-interleukin-2 monoclonal antibody complex (interleukin-2 complex; n=31) or PBS (n=29). Eighty-one percent of angiotensin II-infused mice developed AAA, with 42% mortality possibly because of aneurysm rupture. Interleukin-2 complex treatment systemically increased the number of Foxp3(+) Tregs and significantly decreased the incidence (52%) and mortality (17%) of AAA. Immunohistochemical analysis showed reduced accumulation of macrophages and increased numbers of Foxp3(+) Tregs in aneurysmal tissues, suggesting that expansion of Tregs may suppress local inflammation in the vessel wall and provide protection against AAA formation. Furthermore, genetic depletion of Foxp3(+) Tregs led to a significant increase in the mortality of AAA, suggesting the protective role of Foxp3(+) Tregs against AAA. Our findings suggest that Foxp3(+) Tregs may play a protective role in AAA formation and that promotion of an endogenous regulatory immune response may be a potentially valuable therapeutic approach for preventing AAA.
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan (K.Y., T.Y., N.S., K.K., T.E., T.M., T.K., Y.S., T.M., K.-i.H.); and Institute of Infection Immunology, TWINCORE, Center for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany (T.S.).
authors.forename: Keiko
authors.initials: K
authors.lastname: Yodoi
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan (K.Y., T.Y., N.S., K.K., T.E., T.M., T.K., Y.S., T.M., K.-i.H.); and Institute of Infection Immunology, TWINCORE, Center for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany (T.S.). tomoya@med.kobe-u.ac.jp sasakin@med.kobe-u.ac.jp.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan (K.Y., T.Y., N.S., K.K., T.E., T.M., T.K., Y.S., T.M., K.-i.H.); and Institute of Infection Immunology, TWINCORE, Center for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany (T.S.). tomoya@med.kobe-u.ac.jp sasakin@med.kobe-u.ac.jp.
authors.forename: Naoto
authors.initials: N
authors.lastname: Sasaki
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan (K.Y., T.Y., N.S., K.K., T.E., T.M., T.K., Y.S., T.M., K.-i.H.); and Institute of Infection Immunology, TWINCORE, Center for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany (T.S.).
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kasahara
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan (K.Y., T.Y., N.S., K.K., T.E., T.M., T.K., Y.S., T.M., K.-i.H.); and Institute of Infection Immunology, TWINCORE, Center for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany (T.S.).
authors.forename: Takuo
authors.initials: T
authors.lastname: Emoto
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan (K.Y., T.Y., N.S., K.K., T.E., T.M., T.K., Y.S., T.M., K.-i.H.); and Institute of Infection Immunology, TWINCORE, Center for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany (T.S.).
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan (K.Y., T.Y., N.S., K.K., T.E., T.M., T.K., Y.S., T.M., K.-i.H.); and Institute of Infection Immunology, TWINCORE, Center for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany (T.S.).
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kita
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan (K.Y., T.Y., N.S., K.K., T.E., T.M., T.K., Y.S., T.M., K.-i.H.); and Institute of Infection Immunology, TWINCORE, Center for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany (T.S.).
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan (K.Y., T.Y., N.S., K.K., T.E., T.M., T.K., Y.S., T.M., K.-i.H.); and Institute of Infection Immunology, TWINCORE, Center for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany (T.S.).
authors.forename: Taiji
authors.initials: T
authors.lastname: Mizoguchi
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan (K.Y., T.Y., N.S., K.K., T.E., T.M., T.K., Y.S., T.M., K.-i.H.); and Institute of Infection Immunology, TWINCORE, Center for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany (T.S.).
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan (K.Y., T.Y., N.S., K.K., T.E., T.M., T.K., Y.S., T.M., K.-i.H.); and Institute of Infection Immunology, TWINCORE, Center for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany (T.S.).
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hirata
mesh_terms: D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D007111:Immunity, Cellular; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000804:Angiotensin II
keywords: T-lymphocytes, regulatory; aortic aneurysm, abdominal; immunology; inflammation; interleukin-2