Department of Cell Death and Proliferation, IIBB, CSIC, IDIBAPS, 08036, Barcelona, Spain.
Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, 08036, Barcelona, Spain.
Biol Sex Differ. 2023 Nov 14;14(1):85. 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.
代谢功能障碍相关脂肪性肝病（MASLD）在西方国家较为普遍，随着代谢功能障碍相关脂肪性肝炎（MASH）的发生，存在性别二态性。生育期女性发生 MASLD 的风险低于男性，而绝经后则降低。虽然 NKT 细胞在脂肪性肝炎中的作用存在争议，但差异可能源于所使用的不同小鼠品系，主要是 C57BL6/J 品系，其具有 Th1 优势反应。使用 Th2 优势免疫反应的 Balb/c 背景和缺乏 CD1d 的 Balb/c 背景（缺乏 I 型和 II 型 NKT 细胞）的雄性和雌性小鼠来探索脂肪性肝炎，可以阐明性别差异和 NKT 细胞对 MASH 进展的影响。
雄性和雌性小鼠使用高脂肪和胆碱缺乏（HFCD）饮食，Balb/c 小鼠或缺乏 CD1d 的 Balb/c 背景下的 CD1d 小鼠，这些小鼠表现出 Th2 优势免疫反应。通过 qPCR 和组织学评估测量肝纤维化和炎症基因表达。通过流式细胞术评估 NKT 细胞、T 细胞、巨噬细胞和中性粒细胞。
雌性小鼠在 HFCD 后 6 周表现出较轻的脂肪性肝炎，与雄性相比，肝损伤、炎症和纤维化程度降低。雄性 Balb/c 小鼠的 NKT 细胞具有抗脂肪性肝炎的保护作用，而 HFCD 处理的 CD1d 雄性小鼠的肝保护作用降低，肝纤维化、炎症、中性粒细胞浸润和炎症性巨噬细胞增加。相反，在雌性小鼠的早期脂肪性肝炎发展中，NKT 细胞的作用可以忽略不计，尽管 CD1d 雌性小鼠的肝损伤增加，但纤维化和炎症相似。相关地，雌性 Balb/c 小鼠的肝内 I 型 NKT 细胞水平明显低于雄性。
NKT 细胞对实验性脂肪性肝炎具有保护作用，因为 HFCD 处理的 CD1d 雄性小鼠的纤维化和炎症比雄性 Balb/c 小鼠更严重。在女性中，HFCD 诱导的肝细胞损伤和免疫反应在早期脂肪性肝炎进展中受 NKT 细胞的影响较小，这突出了性别特异性 NKT 细胞对 MASH 发展的影响。
