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

Inflammation promotes heart failure (HF) development, and inhibition of IL-12β simultaneously attenuates interleukin-12 (IL-12) and interleukin-23 (IL-23), two important proinflammatory cytokines. In this study, we used IL-12β knockout (KO) mice to test the hypothesis that genetic inhibition of IL-12β would attenuate transverse aortic constriction (TAC)-induced cardiac inflammation, hypertrophy, and dysfunction, as well as the consequent lung remodeling. IL-12β 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-12β 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-12β KO significantly attenuated TAC-induced LV leukocyte infiltration, cardiomyocyte hypertrophy, fibrosis, and the consequent lung inflammation and remodeling. Moreover, IL-12β 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-12β 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-12β KO mice showed significantly reduced IFNγ CD8 and CXCR3 CD8 T cells in the drainage lymph nodes as compared with WT after TAC. These findings collectively demonstrate that IL-12β plays a critical role in systolic overload-induced LV inflammation, remodeling, and dysfunction, likely through cardiac immune cell infiltration.