Role of Interleukin‐17A in Contributing to the Central Inflammation in Rats with Heart Failure‐Induced by Myocardial Infarction

Inflammation and immune activation have been implicated in the progression of heart failure (HF). The cytokine interleukin (IL)‐17A (commonly known as IL‐17), is a key inflammatory regulator orchestrating immune responses to promote chronic inflammation. IL‐17A has been identified as an important inflammatory mediator in the pathogenesis of several autoimmune diseases. However, emerging evidence indicated that IL‐17A also contributes to the pathophysiology in cardiovascular diseases. We previously reported that peripherally administrated IL‐17A acts within the brain to upregulate the expression of a variety of inflammatory cytokines and chemokines and dramatically increase hemodynamic responses and sympathetic outflow. The IL‐17 receptor A (IL‐17RA) is substantially expressed in the hypothalamic paraventricular nucleus (PVN), a key cardiovascular/autonomic brain center. The present study sought to determine whether IL‐17A level is elevated in HF and, if so, whether increased IL‐17A contributes to the central inflammation in this disease setting. Adult male Sprague Dawley rats were studied 4 weeks after coronary artery ligation to induce HF, or sham‐operation (Sham). Myocardial infarction in HF was confirmed by echocardiography. IL‐17A concentration in plasma and cerebrospinal fluid (CSF) was measured by ELISA and mRNA for IL‐17A, IL‐17F, tumor necrosis factor‐α (TNF‐α), IL‐1β, IL‐6, monocyte chemoattractant protein‐1 (MCP‐1), macrophage inflammatory protein‐1α (MIP‐1α) and stromal cell‐derived factor‐1 (SDF‐1) in PVN was measured by real‐time qPCR. Compared with Sham rats, HF rats had significantly (*P<0.05) increased IL‐17A level in plasma (3.57±0.19* vs 18.4 ± 3.57 pg/ml) and CSF (2.70± 0.34 * vs 6.96 ± 1.08 pg/ml). IL‐17A level in CSF was correlated (R 2 =0.86, p<0.01) with IL‐17A level in plasma. The mRNA levels of IL‐17A (2.53 ± 0.28* vs 1.02± 0.11, fold change) and IL‐17F (2.24 ± 0.22* vs 1.01 ± 0.09) were also higher in HF vs. Sham rats. Immunostaining revealed that IL‐17RA was upregulated in the PVN in HF compared with Sham animals. In HF pretreated with bilateral PVN microinjections of an IL‐17RA siRNA AAV virus and studied two week later, the mRNA level of TNF‐α (1.44 ± 0.18* vs. 2.25 ± 0.21), IL‐1β (1.72 ± 0.21* vs. 2.77 ± 0.25), IL‐6 (1.60 ± 0.17 * vs 2.41 ± 0.21), MCP‐1 (2.09 ± 0.18* vs 3.19 ± 0.27), MIP‐α (1.62 ± 0.15* vs 2.39 ± 0.22) and SDF‐1 (1.68 ± 0.24* vs 2.72 ± 0.23) were significantly reduced in the PVN compared with the HF rats pretreated with a scrambled siRNA virus. Sham rats without any treatments served as control. Knockdown efficiency of IL‐17RA siRNA was confirmed by a reduction (‐55%) of IL‐17RA mRNA level in the PVN. These data indicated that IL‐17A increases in HF and upregulates the expression of cytokines and chemokines in the brain. The increased IL‐17A advances central inflammatory condition in HF probably by evoking the production of various inflammatory mediators. IL‐17A is a potential target for therapeutic intervention in HF.