Overexpression of SOCS3 in T lymphocytes leads to impaired interleukin-17 production and severe aortic aneurysm formation in mice-brief report

Mélissa Romain, Soraya Taleb, Marion Dalloz, Padmapriya Ponnuswamy, Bruno Esposito, Nicolas Pérez, Yu Wang, Akihiko Yoshimura, Alain Tedgui, Ziad Mallat

研究成果: Article

28 引用 (Scopus)

抄録

Objective-Mutations of signal transducer and activator of transcription 3 (STAT3) are responsible for autosomal dominant hyperimmunoglobulin E syndrome. Recently, we reported frequent vascular abnormalities, including aneurysms in these patients, and demonstrated that STAT3 inhibition promoted aneurysm in mice. The purpose of this study was to investigate the role of cell-specific STAT3 signaling in the susceptibility to aneurysm. Methods and Results-C57BL/6 wild-type mice were irradiated and repopulated with bone marrow cells isolated from either wild-type mice or from mice with defective STAT3 signaling as a result of overexpression of suppressor of cytokine signaling 3 (SOCS3-Tg mice). Mice were then subjected to a validated model of abdominal aortic aneurysm induced by angiotensin II infusion for 28 days, along with repetitive injections of a neutralizing antitransforming growth factor-β antibody. We found that overexpression of SOCS3 in bone marrow-derived cells significantly increased aneurysm severity (P=0.04). In contrast, overexpression of SOCS3 in the vessel wall had no effect on the disease process. Surprisingly, deletion of STAT3 signaling in macrophages did not affect aneurysm development. Interestingly, however, defective STAT3 signaling in SOCS3-Tg T cells markedly increased aneurysm severity (P=0.01) and mortality from aneurysm rupture (P=0.008). Overexpression of SOCS3 in T cells significantly decreased interleukin-17 production (P<0.0001) and was associated with a reduction of its plasma levels (P=0.02). Conclusion-These findings clearly identify a central role for T cell-specific STAT3 signaling in the promotion of vascular aneurysm and support previous work on interleukin-17 protective role in this process.

元の言語English
ページ(範囲)581-584
ページ数4
ジャーナルArteriosclerosis, Thrombosis, and Vascular Biology
33
発行部数3
DOI
出版物ステータスPublished - 2013 3

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Interleukin-17
Aortic Aneurysm
STAT3 Transcription Factor
Aneurysm
T-Lymphocytes
Bone Marrow Cells
Blood Vessels
Abdominal Aortic Aneurysm
Angiotensin II
Rupture
Intercellular Signaling Peptides and Proteins
Macrophages
Cytokines
Mutation
Injections
Mortality
Antibodies

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

これを引用

Overexpression of SOCS3 in T lymphocytes leads to impaired interleukin-17 production and severe aortic aneurysm formation in mice-brief report. / Romain, Mélissa; Taleb, Soraya; Dalloz, Marion; Ponnuswamy, Padmapriya; Esposito, Bruno; Pérez, Nicolas; Wang, Yu; Yoshimura, Akihiko; Tedgui, Alain; Mallat, Ziad.

:: Arteriosclerosis, Thrombosis, and Vascular Biology, 巻 33, 番号 3, 03.2013, p. 581-584.

研究成果: Article

Romain, Mélissa ; Taleb, Soraya ; Dalloz, Marion ; Ponnuswamy, Padmapriya ; Esposito, Bruno ; Pérez, Nicolas ; Wang, Yu ; Yoshimura, Akihiko ; Tedgui, Alain ; Mallat, Ziad. / Overexpression of SOCS3 in T lymphocytes leads to impaired interleukin-17 production and severe aortic aneurysm formation in mice-brief report. :: Arteriosclerosis, Thrombosis, and Vascular Biology. 2013 ; 巻 33, 番号 3. pp. 581-584.
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AU - Taleb, Soraya

AU - Dalloz, Marion

AU - Ponnuswamy, Padmapriya

AU - Esposito, Bruno

AU - Pérez, Nicolas

AU - Wang, Yu

AU - Yoshimura, Akihiko

AU - Tedgui, Alain

AU - Mallat, Ziad

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N2 - Objective-Mutations of signal transducer and activator of transcription 3 (STAT3) are responsible for autosomal dominant hyperimmunoglobulin E syndrome. Recently, we reported frequent vascular abnormalities, including aneurysms in these patients, and demonstrated that STAT3 inhibition promoted aneurysm in mice. The purpose of this study was to investigate the role of cell-specific STAT3 signaling in the susceptibility to aneurysm. Methods and Results-C57BL/6 wild-type mice were irradiated and repopulated with bone marrow cells isolated from either wild-type mice or from mice with defective STAT3 signaling as a result of overexpression of suppressor of cytokine signaling 3 (SOCS3-Tg mice). Mice were then subjected to a validated model of abdominal aortic aneurysm induced by angiotensin II infusion for 28 days, along with repetitive injections of a neutralizing antitransforming growth factor-β antibody. We found that overexpression of SOCS3 in bone marrow-derived cells significantly increased aneurysm severity (P=0.04). In contrast, overexpression of SOCS3 in the vessel wall had no effect on the disease process. Surprisingly, deletion of STAT3 signaling in macrophages did not affect aneurysm development. Interestingly, however, defective STAT3 signaling in SOCS3-Tg T cells markedly increased aneurysm severity (P=0.01) and mortality from aneurysm rupture (P=0.008). Overexpression of SOCS3 in T cells significantly decreased interleukin-17 production (P<0.0001) and was associated with a reduction of its plasma levels (P=0.02). Conclusion-These findings clearly identify a central role for T cell-specific STAT3 signaling in the promotion of vascular aneurysm and support previous work on interleukin-17 protective role in this process.

AB - Objective-Mutations of signal transducer and activator of transcription 3 (STAT3) are responsible for autosomal dominant hyperimmunoglobulin E syndrome. Recently, we reported frequent vascular abnormalities, including aneurysms in these patients, and demonstrated that STAT3 inhibition promoted aneurysm in mice. The purpose of this study was to investigate the role of cell-specific STAT3 signaling in the susceptibility to aneurysm. Methods and Results-C57BL/6 wild-type mice were irradiated and repopulated with bone marrow cells isolated from either wild-type mice or from mice with defective STAT3 signaling as a result of overexpression of suppressor of cytokine signaling 3 (SOCS3-Tg mice). Mice were then subjected to a validated model of abdominal aortic aneurysm induced by angiotensin II infusion for 28 days, along with repetitive injections of a neutralizing antitransforming growth factor-β antibody. We found that overexpression of SOCS3 in bone marrow-derived cells significantly increased aneurysm severity (P=0.04). In contrast, overexpression of SOCS3 in the vessel wall had no effect on the disease process. Surprisingly, deletion of STAT3 signaling in macrophages did not affect aneurysm development. Interestingly, however, defective STAT3 signaling in SOCS3-Tg T cells markedly increased aneurysm severity (P=0.01) and mortality from aneurysm rupture (P=0.008). Overexpression of SOCS3 in T cells significantly decreased interleukin-17 production (P<0.0001) and was associated with a reduction of its plasma levels (P=0.02). Conclusion-These findings clearly identify a central role for T cell-specific STAT3 signaling in the promotion of vascular aneurysm and support previous work on interleukin-17 protective role in this process.

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