γδT Cell-derived interleukin-17A via an interleukin-1β-dependent mechanism mediates cardiac injury and fibrosis in hypertension.

Abstract

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-17A+CD3+ 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.