Heart failure (HF) is the most common reason for hospitalization and death among those older than 65 years,
and statistic is projected to grow as our population ages. The socioeconomic impact of HF on our health care
system is enormous. Development of innovative approaches to the treatment of HF is therefore a top research
priority. Although inflammation and immune activation have been implicated in the pathophysiology of HF over
the past two decades, the progress for development of new pharmaceutical agents targeting this mechanism
was stagnant, especially given that several anti-cytokine clinical trials targeting a single effector cytokine at the
peripheral manifestations of HF did not produce clinical benefits. Obviously, the inflammatory mechanisms
underlying the pathogenesis of HF have not been challenged. The proposed project studying a role of brain
interleukin (IL)-17A (previously known as IL-17) in advancing central inflammation, sympathetic activation and
cardiac dysfunction will address the need for a better understanding of the inflammatory mechanisms in HF
and provide a novel anti-cytokine approach in treating this devastating disease. The research plan was
developed based on the intrinsic property of IL-17A and our compelling preliminary data: 1) IL-17A is a kay
inflammatory regulator bridging immune responses and tissue inflammation; 2) It boosts the expression of a
broad spectrum of inflammatory mediators in the brain and in the peripheral tissue and cells; 3) Systemic and
central administration of IL-17A induced dramatic and long-lasting increases in blood pressure, heart rate and
renal sympathetic nerve activity to the levels not seen by other pre-inflammatory cytokines; 4) levels of IL-17A
in the plasma, cerebrospinal fluid, and paraventricular nucleus of hypothalamus (PVN, a key cardiovascular
and autonomic center of the brain) are higher in a rat model of HF vs. in sham-operated (Sham) animals; and 5)
Its receptor, IL-17RA, is highly expressed in the PVN and substantially upregulated in HF. Using a multifaceted
approach including electrophysiology, molecular biology, immunocytochemistry, pharmacology, biochemistry
and neuroscience in Sham and HF rats, this project will: 1) identify the role of IL-17A in advancing central
inflammation in HF; 2) determine the inflammatory mechanisms whereby IL-17A triggers sympathetic activation
in HF; 3) evaluate the protective effect of central interventions targeting the IL-17A signaling, alone or in
combination with other cytokines in HF. The proposed research will target a master regulator of inflammation
rather than a single effector cytokine as a novel anti-cytokine strategy in treating HF, and consider the
synergistic actions of multiple cytokines as a potentially more effective means of ameliorating HF. The
proposed studies will characterize a previously unrecognized role of brain IL-17A in sympathetic activation and
test its potential as a target in treating cardiac dysfunction of HF. Completion of this research project will
provide important insights into the anti-inflammation therapeutic strategy in HF and may carry the implication
for other cardiovascular disorders like hypertension and metabolic diseases like obesity or diabetes.