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Published on: May 29, 2020
Sex-based differences in natural killer T cell-mediated protection against diet-induced steatohepatitis in Balb/c
Carlos Cuño-Gómiz1,2, Estefanía de Gregorio1, Anna Tutusaus1
1Department of Cell Death and Proliferation, IIBB, CSIC, IDIBAPS, 08036, Barcelona, Spain.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
NKT cells protect against metabolic dysfunction-associated steatohepatitis (MASH) in males, but this effect is diminished in females. This study highlights sex-specific NKT-cell roles in MASH development and progression.
Area of Science:
- Hepatology
- Immunology
- Metabolic Diseases
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) affects Western populations and can progress to MASLD, with observed gender differences in prevalence.
- Fertile women have a lower risk of MASLD than men, a difference that lessens after menopause.
- The role of NKT cells in steatohepatitis is debated, potentially due to variations in mouse models and immune responses (Th1 vs. Th2).
Purpose of the Study:
- To investigate the sex-specific role of NKT cells in the development and progression of metabolic dysfunction-associated steatohepatitis (MASH).
- To clarify gender disparities in MASH by using mouse models with different immune responses (Th2-dominant) and NKT-cell deficiencies.
Main Methods:
- Male and female mice (Balb/c and CD1d-deficient on Balb/c background) were fed a high-fat choline-deficient (HFCD) diet.
- Liver fibrosis, inflammation, and gene expression were quantified using qPCR and histology.
- Immune cell populations (NKT cells, T cells, macrophages, neutrophils) were analyzed via flow cytometry.
Main Results:
- Female mice showed milder steatohepatitis, with less liver damage, inflammation, and fibrosis compared to males after HFCD diet.
- In males, NKT cells conferred protection against steatohepatitis, while CD1d-deficient males exhibited exacerbated liver injury and inflammation.
- NKT cells had a negligible role in early steatohepatitis development in females, despite similar liver damage in CD1d-deficient females.
Conclusions:
- NKT cells play a protective role in experimental steatohepatitis, particularly in males.
- The influence of NKT cells on MASH progression is sex-specific, with a less pronounced effect observed in females during early stages.
