Abstract Body: Background T helper 17 (Th17) cells and their signature cytokine IL-17A exacerbate chronic inflammation following myocardial infarction (MI), contributing to adverse cardiac remodeling and heart failure. Although peptidergic sensory neurons have been shown to modulate inflammatory responses through neuropeptide signaling, the role of neuropeptide-driven mechanisms in post-MI Th17 inflammation remains unexplored.
Hypothesis and Aims We hypothesized that substance P (SP) released from cardiac sensory neurons and its receptor neurokinin-1 receptor (NK1R) drive Th17 inflammation and subsequent cardiac dysfunction post-MI. This study aimed to determine whether genetic disruption of SP/NK1R signaling attenuates Th17 inflammation and improves post-MI cardiac function.
Methods and Results An MI model was induced in adult male C57BL/6 mice via permanent coronary artery ligation. Serial echocardiography revealed progressive deterioration of left ventricular ejection fraction (EF) in wild-type (WT) mice, reaching 38% by day 28 post-MI (Fig. 1A, B). Concurrently, cardiac tissue exhibited elevated SP and IL-17A levels (Fig. 1C, D), with significant positive correlation (r=0.6655, p=0.006; Fig. 1E). Genetic ablation of NK1R (NK1R^-/-) markedly preserved cardiac function at all timepoints post-MI compared to WT controls (Fig. 1F, G), accompanied by reduced cardiac SP and IL-17A levels (Fig. 1H, I). Flow cytometric analysis demonstrated that NK1R deficiency attenuated MI-induced infiltration of CD4⁺ T cells (WT 18.6 % vs NK1R^-/- 12.4 %, p=0.0031, Fig.1 J, L) and specifically suppressed Th17 cell accumulation (WT 11.0 % vs NK1R^-/- 5.2 %, p=0.0045, Fig.1 K, M) in infarcted myocardium at 14d post-MI.
Conclusions Our findings establish SP/NK1R signaling as a critical regulator of Th17 inflammation and cardiac dysfunction post-MI. Targeted inhibition of this neuroimmunological axis may represent a novel therapeutic strategy to alleviate cardiac inflammation and heart failure after ischemic injury.