Cardiomyocyte-derived IL-30 improves cardiac repair by reducing splenic germinal center activation after myocardial infarction.

Abstract

Following myocardial infarction (MI), splenic humoral immune responses contribute to cardiac injury and repair, yet the cardiac signals that govern these responses remain poorly defined. Here, we identified ischemic cardiomyocytes as a source of interleukin 30 (IL-30; the interleukin 27 p28 subunit) and investigated its role in heart-spleen communication. In mice, cardiomyocyte-specific IL-30 deficiency enhanced splenic germinal center responses and signal transducer and activator of transcription 1 (STAT1) phosphorylation. This deficiency increased myocardial IgG deposition, TNF-α expression in Fc gamma receptor III-positive macrophages, and cardiomyocyte apoptosis, while impairing cardiac function and aggravating ventricular remodeling. Recombinant IL-30 suppressed splenic germinal center responses and STAT1 phosphorylation and improved cardiac function. The effects of recombinant IL-30 on germinal center responses and cardiac function were abolished by B cell-specific deletion of glycoprotein 130 (gp130). Furthermore, no detectable improvement in cardiac function was observed following IL-30 treatment in splenectomized mice. In patients with ST-segment elevation myocardial infarction (STEMI; n = 75), lower circulating IL-30 levels were associated with higher peripheral IgG-positive B cell frequencies. In a separate longitudinal cohort of 247 patients with STEMI, low circulating IL-30 was independently associated with adverse left ventricular remodeling at 6 months (odds ratio, 4.44; 95% confidence interval, 2.16-9.80; P< 0.001). Circulating IL-30 discriminated patients with and without adverse remodeling with an area under the receiver operating characteristic curve of 0.738. These findings identify cardiomyocyte-derived IL-30 as an endogenous regulator of heart-spleen communication that restrains splenic humoral responses and limits adverse cardiac remodeling after MI.