Genetic inhibition of IL-12β suppresses systolic overload-induced cardiac inflammation and heart failure development

Abstract

Inflammation promotes heart failure (HF) development, and inhibition of IL-12{beta} simultaneously attenuates interleukin-12 (IL-12) and interleukin-23 (IL-23), two important proinflammatory cytokines. In this study, we used IL-12{beta} knockout (KO) mice to test the hypothesis that genetic inhibition of IL-12{beta} would attenuate transverse aortic constriction (TAC)-induced cardiac inflammation, hypertrophy, and dysfunction, as well as the consequent lung remodeling. IL-12{beta} KO in male and female mice significantly attenuated TAC-induced cardiac dysfunction as evidenced by improved left ventricular (LV) ejection fraction and fractional shortening. IL-12{beta} KO also significantly ameliorated the TAC-induced increase of LV weight, left atrial weight, lung weight, right ventricular (RV) weight, and their ratios to body weight or tibial length in male and female mice. In addition, IL-12{beta} KO significantly attenuated TAC-induced LV leukocyte infiltration, cardiomyocyte hypertrophy, fibrosis, and the consequent lung inflammation and remodeling. Moreover, IL-12{beta} KO reduced TAC-induced alterations of LV gene profile associated with inflammation and fibrosis, as shown by bulk LV RNA sequencing. Furthermore, we found that IL-12{beta} KO significantly attenuated TAC-induced LV accumulation of multiple immune cell subsets, activation of CD4+ and CD8+ T cells, and the percentage of central memory CD4+ and CD8+ T cells in the cardiac drainage lymph nodes. Finally, IL-12{beta} KO mice showed significantly reduced IFN{gamma}+CD8+ and CXCR3+CD8+ T cells in the drainage lymph nodes as compared with WT after TAC. These findings collectively demonstrate that IL-12{beta} plays a critical role in systolic overload-induced LV inflammation, remodeling, and dysfunction, likely through cardiac immune cell infiltration.