γδT Cell–Derived Interleukin-17A via an Interleukin-1β–Dependent Mechanism Mediates Cardiac Injury and Fibrosis in Hypertension

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2014-08, Vol.64 (2), p.305-314
• Main Authors: Li, Yulin, Wu, Yina, Zhang, Congcong, Li, Ping, Cui, Wei, Hao, Jianlei, Ma, Xinliang, Yin, Zhinan, Du, Jie
• Format: Article
• Language: English
• Subjects: Angiotensin II; Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Fibrosis - metabolism; Fibrosis - pathology; Hypertension - chemically induced; Hypertension - metabolism; Hypertension - pathology; Interleukin-17 - metabolism; Interleukin-1beta - metabolism; Interleukin-6 - metabolism; Medical sciences; Mice; Myocardium - metabolism; Myocardium - pathology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Transforming Growth Factor beta - metabolism
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.113.02604

Inflammation is implicated in the initiation of hypertension and end-organ injury. Interleukin-17A (IL-17A) is a key pathogenic factor in a variety of inflammatory diseases and hypertension. However, the mechanisms underlying IL-17A production, and its role in mediating inflammation and early cardiovascular injury in hypertensive heart, remain unknown. Angiotensin II (Ang II) infusion increased cardiac IL-17A mRNA expression and IL-17ACD3 cell infiltration in a time-dependent manner. IL-17A in the hypertensive heart was derived mostly from infiltrating γδT cells rather than from CD4 T cells. Genetic knockdown of γδT cells or specific anti-γδT antibody abolished IL-17A production in Ang II–infused heart. Moreover, monocyte-secreted IL-1β, not cardiac fibroblast–secreted IL-6 or transforming growth factor-β, was required for IL-17A production from γδT cell. IL-17A accelerated differentiation of myofibroblast through promoting IL-6 production from cardiac fibroblast. Finally, inflammatory cell infiltration, proinflammatory or profibrotic cytokine expression, and fibrotic lesion induced by Ang II were attenuated in IL-17A–deficient mice. Moreover, the deletion of γδT cell was protected from Ang II–induced cardiac injury. Thus, a triangular positive feedback loop exists among monocytic-secreted IL-1β, γδT-cell–derived IL-17A, and cardiac fibroblast–produced IL-6, which triggers the cardiac injury in hypertension.