Association between CD4+/PD-1+/CD153+ Cell Infiltration to the Aging Liver and Progression of Hepatic Steatosis in A Novel MASH Model NI Mouse

Metabolic disorder-associated steatohepatitis (MASH) is one of the most important diseases, which progresses to hepatocellular carcinoma through hepatocellular dysfunction caused by steatosis and fibrosis. Recently, CD4+/programmed cell death 1 (PD-1)+/CD153+ cells [commonly referred to as senescence-associated T (SA-T) cells] have been identified as a senescence-associated secretory phenotype that produces chronic inflammation factors in a paracrine manner involved in osteopontin (OPN)-induced signal for the progression of steatosis in aging hepatocytes via anti-apoptosis, alanine amino-transferase (ALT) release, and so on. However, the detailed mechanisms are not fully elucidated. We identified a novel strain Nishiura (NI) mouse fed a normal diet that macroscopically showed yellowish orange discoloration of the liver at 36 weeks of age, followed by tumor-like masses at 48 weeks of age through a decrease in Lineage-/CD34-/c-kit+/sca-1+ stem cells in the bone marrow and an increase in SA-T cells in the spleen at 24 weeks of age, infiltration of OPN+ or CD153+ cells in the PD-1+ liver at 36 weeks of age, and an increase in plasma OPN at 48 weeks of age. Conversely, SA-T cells, but not CD4+/PD-1+/CD153- cells, prepared from 36-week-old spleens of NI mice were transplanted in 12-week-old spleens of NI mice, but not into those of B6 mice, inducing severe hepatic steatosis and fibrosis at 36 weeks of age with an increase in OPN in liver extract. Furthermore, in a cohort study, SA-T cell rate in the biopsy specimen showed a positive correlation with the hepatitis activity index in patients with steatosis aged at least 60 years or older. In this paper, we discovered an association between CD4+/PD-1+/CD153+ cell infiltration to the aging liver and progression of hepatic steatosis in a novel MASH model NI mouse.