Sex-based differences in natural killer T cell-mediated protection against diet-induced steatohepatitis in Balb/c mice

• Published in: Biology of sex differences Vol. 14; no. 1; p. 85
• Main Authors: Cuño-Gómiz, Carlos, de Gregorio, Estefanía, Tutusaus, Anna, Rider, Patricia, Andrés-Sánchez, Nuria, Colell, Anna, Morales, Albert, Marí, Montserrat
• Format: Journal Article
• Language: English
• Published: England BioMed Central 14-11-2023; BMC
• Subjects: Adaptive immunology; Animals; Antigens; CD1d antigen; Choline; Cytokines; Diet, High-Fat; Diet, High-Fat - adverse effects; Endocrinology and metabolism; Fatty Liver; Fatty Liver - metabolism; Fatty Liver - pathology; Female; Females; Fibrosis; Flow cytometry; Gene expression; Hepatic NKT cells; High fat diet; Human health and pathology; Humans; Hépatology and Gastroenterology; Immune system; Immunology; Inflammation; Laboratory animals; Leukocytes (neutrophilic); Life Sciences; Liver Cirrhosis; Liver Cirrhosis - pathology; Liver diseases; Lymphocytes; Lymphocytes T; Macrophages; Male; Males; Menopause; Metabolic dysfunction-associated steatohepatitis (MASH); Metabolic dysfunction-associated steatotic liver disease (MASLD); Metabolism; Mice; Mice, Inbred BALB C; Natural killer cells; Natural Killer T-Cells; Natural Killer T-Cells - pathology; Natural Killer T-Cells - physiology; Non-alcoholic fatty liver disease (NAFLD); Non-alcoholic steatohepatitis (NASH); Nutrient deficiency; Post-menopause; Sex Characteristics; Sex differences; Sexual dimorphism; T cell receptors; Womens health; Liver; Metabolic dysfunction-associated steatohepatitis (MASH); Non-alcoholic fatty liver disease (NAFLD); Hepatic NKT cells; Sex differences; Inflammation; CD1d; Metabolic dysfunction-associated steatotic liver disease (MASLD); Non-alcoholic steatohepatitis (NASH)
• ISSN: 2042-6410; 2042-6410
• DOI: 10.1186/s13293-023-00569-w

Metabolic dysfunction-associated steatotic liver disease (MASLD) is prevalent in Western countries, evolving into metabolic dysfunction-associated steatohepatitis (MASH) with a sexual dimorphism. Fertile women exhibit lower MASLD risk than men, which diminishes post-menopause. While NKT-cell involvement in steatohepatitis is debated, discrepancies may stem from varied mouse strains used, predominantly C57BL6/J with Th1-dominant responses. Exploration of steatohepatitis, encompassing both genders, using Balb/c background, with Th2-dominant immune response, and CD1d-deficient mice in the Balb/c background (lacking Type I and Type II NKT cells) can clarify gender disparities and NKT-cell influence on MASH progression.
A high fat and choline-deficient (HFCD) diet was used in male and female mice, Balb/c mice or CD1d
mice in the Balb/c background that exhibit a Th2-dominant immune response. Liver fibrosis and inflammatory gene expression were measured by qPCR, and histology assessment. NKT cells, T cells, macrophages and neutrophils were assessed by flow cytometry.
Female mice displayed milder steatohepatitis after 6 weeks of HFCD, showing reduced liver damage, inflammation, and fibrosis compared to males. Male Balb/c mice exhibited NKT-cell protection against steatohepatitis whereas CD1d
males on HFCD presented decreased hepatoprotection, increased liver fibrosis, inflammation, neutrophilic infiltration, and inflammatory macrophages. In contrast, the NKT-cell role was negligible in early steatohepatitis development in both female mice, as fibrosis and inflammation were similar despite augmented liver damage in CD1d
females. Relevant, hepatic type I NKT levels in female Balb/c mice were significantly lower than in male.
NKT cells exert a protective role against experimental steatohepatitis as HFCD-treated CD1d
males had more severe fibrosis and inflammation than male Balb/c mice. In females, the HFCD-induced hepatocellular damage and the immune response are less affected by NKT cells on early steatohepatitis progression, underscoring sex-specific NKT-cell influence in MASH development.