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

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Biology of Sex Differences Pub Date : 2023-11-14 DOI:10.1186/s13293-023-00569-w
Carlos Cuño-Gómiz, Estefanía de Gregorio, Anna Tutusaus, Patricia Rider, Nuria Andrés-Sánchez, Anna Colell, Albert Morales, Montserrat Marí
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Abstract

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.

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Balb/c小鼠中自然杀伤T细胞介导的抗饮食性脂肪性肝炎保护的性别差异
背景:代谢功能障碍相关的脂肪性肝病(MASLD)在西方国家很普遍,并演变为代谢功能障碍相关的脂肪性肝炎(MASH)伴性别二态性。有生育能力的女性比男性表现出更低的MASLD风险,这在绝经后会减少。虽然nkt细胞参与脂肪性肝炎仍有争议,但差异可能源于使用的不同小鼠品系,主要是C57BL6/J与th1主导应答。研究包括两性在内的脂肪性肝炎,使用Balb/c背景,以th2为主的免疫反应,以及Balb/c背景的cd1缺陷小鼠(缺乏I型和II型NKT细胞),可以澄清性别差异和NKT细胞对MASH进展的影响。方法:采用高脂胆碱缺乏(HFCD)饮食,分别饲喂雄性和雌性小鼠、Balb/c小鼠或Balb/c背景下表现出th2显性免疫反应的CD1d-/-小鼠。采用qPCR检测肝纤维化和炎症基因表达,并进行组织学评估。流式细胞术检测NKT细胞、T细胞、巨噬细胞和中性粒细胞。结果:与雄性小鼠相比,雌性小鼠在HFCD治疗6周后表现出较轻的脂肪性肝炎,表现出较轻的肝损伤、炎症和纤维化。雄性Balb/c小鼠对脂肪性肝炎表现出nkt细胞保护作用,而CD1d-/-雄性HFCD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。相比之下,在两种雌性小鼠中,nkt细胞在早期脂肪性肝炎发展中的作用可以忽略不计,因为尽管CD1d-/-雌性小鼠的肝损伤增强,但纤维化和炎症相似。与此相关,雌性Balb/c小鼠肝脏I型NKT水平显著低于雄性。结论:NKT细胞对实验性脂肪性肝炎具有保护作用,CD1d-/-雄性小鼠比Balb/c雄性小鼠有更严重的纤维化和炎症。在女性中,hfcd诱导的肝细胞损伤和免疫应答在早期脂肪性肝炎进展中较少受到NKT细胞的影响,这强调了NKT细胞在MASH发展中的性别特异性影响。
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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
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