Heart failure (HF) is the end stage of many cardiovascular diseases and is a threat to human life. HF endangers approximately 40 million people worldwide (Baman JR and Ahmad FS, 2020). It manifests as a multifactorial systemic disease and includes myocardial injury, ischemia, and other factors that trigger an immune inflammatory response, which promotes pathological phenotypic changes in myocardial cells and compensatory structural remodeling. Most of the research on immune-inflammatory mechanisms has demonstrated that monocyte-derived macrophages and T cells play vital roles in the progression of HF(Kallikourdis M et al., 2017; Sager HB et al., 2016).

The interleukin (IL)-12 p40 subunit is the common subunit of IL-12 and IL-23 and is expressed by various antigen-presenting cells (APCs) (Vignali DA and Kuchroo VK, 2012), such as macrophages (Mø), dendritic cells (DCs), and microglia. IL-12p40 is produced by activated inflammatory immune cells but plays complex and variable roles in different inflammatory microenvironments. Sharma et al. reported that IL-12p40 deficiency contributed to abdominal aortic aneurysm in mice through cellular communication network factor 2 (CCN2)/matrix metalloproteinase-2 (MMP-2) pathway-induced fibrinolysis (Sharma N and Hans CP, 2021). In a chronic allograft rejection mouse model, neutralizing IL-12p40 prolonged graft survival by inhibiting inflammatory γδT cells (Wang S et al., 2012). Okamoto et al. also reported that deletion of IL-12p40 attenuated experimental chronic graft-versus-host disease by reducing the number of proinflammatory interferon (IFN)-γ/IL-17 double-positive cells (Okamoto S et al., 2015). In addition, IL-12p40 serves as a profibrotic factor in pulmonary fibrosis (Huaux F et al., 2002) and plays a role in autoimmune diseases (Kulig P et al., 2016; Lee SY et al., 2015) and in other inflammatory responses (Marks E et al., 2017; Zwicky P et al., 2021).

Cardiac remodeling caused by pressure overload is the main cause of HF. Previous studies have shown that inflammatory cytokines and cells participate in the pathological process of stress-induced cardiac fibrosis and hypertrophy. Wang et al. reported that mixed lineage kinase 3, a proinflammatory cytokine, activates cardiomyocyte pyroptosis and ferroptosis to aggravate cardiac fibrosis in transverse aortic constriction (TAC)-induced mice (Wang J et al., 2020). Our previous study demonstrated that IL-12p40 deletion exacerbates monocyte accumulation and inflammation in lipopolysaccharide-induced cardiac injury by activating the nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways (Liu M et al., 2022). However, whether IL-12p40 participates in pressure overload-induced cardiac remodeling is unknown. In this study, we explored whether IL-12p40 affects immune inflammation in TAC-induced cardiac remodeling and the underlying mechanism.