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

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). CONCLUSIONS 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.