ICF: Neutrophils and cellular senescence: A vicious circle promoting age-related disease.

ICF：中性粒细胞和细胞衰老：促进与年龄相关疾病的恶性循环。

• 批准号: MR/Y003365/1
• 负责人: Derek Mann
• 金额: $ 139.02万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY003365%2F1
• 关键词: ICF; Neutrophils; cellular; senescence; vicious

Chronic liver disease (CLD) is a global health care problem affecting in excess of 1.5 billion people who are at risk of developing cirrhosis and/or a primary liver cancer. Ageing and obesity are major risk factors for the development and progression of liver disease. Of particular concern is non-alcoholic steatohepatitis (NASH) which is a metabolic liver disease associated with obesity and type II diabetes. NASH incidence increases dramatically with ageing, as does the risk of progression of NASH to cirrhosis, indicating a link between ageing and NASH. Moreover, up to 25% of liver cancers that develop on the background of NASH do so in the absence of cirrhosis. NASH is characterised by fatty deposits (steatosis) in the liver, inflammation, scaring (fibrosis) and the presence of damaged (ballooned) and aged (senescent) hepatocytes (predominant liver cell).Cellular senescence is a state in which cells lose their ability to proliferate and also secrete a soup of bioactive molecules that promote wound repair and regeneration, termed the senescence-associated secretory phenotype (SASP). In a young person senescent cells are cleared by the immune system. However, ageing is accompanied by immune decline and reduced efficiency of senescent cell clearance, leading to their accumulation and persistence of the SASP. This can lead to a pathological process where the SASP promotes spread of senescence to bystander cells and stimulates chronic inflammation and maladaptive wound repair. These pathologies being typical features of NASH alongside steatosis.In 2014-2015 we reported in mice that a neutrophil rich persistent low-grade inflammation drives hepatocyte senescence, steatosis, fibrosis, cancer and early death. In 2021 we showed that neutrophils can directly trigger senescence in hepatocytes via oxidative DNA damage. Moreover, we discovered that neutrophils accumulate to a greater extent in the ageing liver and are attracted to senescent hepatocytes. As neutrophils are a classic histopathological characteristic of NASH this is a very significant discovery. In an earlier study, hepatocyte senescence was shown to be necessary and sufficient for steatosis. These observations suggest that neutrophilic inflammation, senescence and steatosis are mechanistically linked. We hypothesise that they combine through positive feedforward signalling pathways to promote age-related NASH, CLD and cancer. To test our hypothesis, we will first carry out experiments that determine the bidirectional feedforward effects of interactions of senescent hepatocytes and neutrophils on the phenotype and function of these two cell types which we predict to be highly dynamic. These experiments will use a bespoke human liver slice technology and genetic experiments carried out in mouse models of induced obesity, steatosis and NASH. We expect to make discoveries that will illuminate how neutrophils and senescent hepatocytes collude to promote inflammation-driven tissue ageing and CLD. We will also include experiments that ask how acute neutrophilic inflammation associated with infections exacerbates NASH, this being relevant to Covid-19 which is reported to aggravate CLD.Secondly, we will ask if our discovery that neutrophils are attracted to senescent cells can be exploited to stimulate the immune system to clear senescent hepatocytes. We will engineer neutrophils to express antibodies at their surface that selectively lock onto proteins expressed at the surface of senescent cells, this aimed at enhancing their physical interaction and in doing so encouraging neutrophil-mediated clearance of senescent cells.By carrying out this 3-year project we will (1) substantially increase knowledge of how inflammation and ageing combine to promote CLD, (2) discover new mechanistic biology of broad interest to biologists and immunologists and (3) learn if neutrophils can be manipulated for immunotherapeutic purposes in ageing- and obesity-related diseases.

慢性肝病（CLD）是一个全球医疗保健问题，影响超过15亿人患有肝硬化和/或原发性肝癌的风险。衰老和肥胖是肝病发展和发展的主要危险因素。特别关注的是非酒精性脂肪性肝炎（NASH），这是一种与肥胖症和II型糖尿病相关的代谢肝病。纳什发病率随着衰老而大大增加，纳什（Nash）向肝硬化的风险也大大增加，表明衰老与纳什（Nash）之间有联系。此外，在没有肝硬化的情况下，在纳什背景中发育的肝癌中多达25％。 NASH is characterised by fatty deposits (steatosis) in the liver, inflammation, scaring (fibrosis) and the presence of damaged (ballooned) and aged (senescent) hepatocytes (predominant liver cell).Cellular senescence is a state in which cells lose their ability to proliferate and also secrete a soup of bioactive molecules that promote wound repair and regeneration, termed the衰老相关的分泌表型（SASP）。在一个年轻人中，衰老细胞被免疫系统清除。然而，衰老伴随着免疫下降和衰老细胞清除效率的降低，导致其积累和持久性SASP。这可能导致一个病理过程，SASP促进衰老到旁观者细胞的扩散并刺激慢性炎症和适应不良的伤口修复。这些病理是纳什（Nash）以及脂肪变性的典型特征。在2014-2015中，我们在小鼠中报道说，富含中性粒细胞的持续性低度炎症驱动肝细胞衰老，脂肪变性，纤维化，纤维化，癌症和早期死亡。在2021年，我们表明中性粒细胞可以通过氧化DNA损伤直接触发肝细胞中的衰老。此外，我们发现嗜中性粒细胞在衰老的肝脏中会更大程度地积累，并被衰老的肝细胞吸引。由于中性粒细胞是纳什的经典组织病理学特征，这是一个非常重要的发现。在较早的研究中，肝细胞衰老被证明是必要的，足以足以进行脂肪变性。这些观察结果表明，嗜中性炎症，衰老和脂肪变性是机械上联系的。我们假设它们通过积极的前馈信号通路结合，以促进与年龄相关的NASH，CLD和癌症。为了检验我们的假设，我们将首先进行实验，以确定衰老肝细胞和中性粒细胞相互作用对这两种细胞类型的表型和功能的双向前进作用，我们预计这是高度动态的。这些实验将使用定制的人肝切片技术和在诱导肥胖，脂肪变性和NASH的小鼠模型中进行的基因实验。我们期望发现中性粒细胞和衰老的肝细胞相交以促进炎症驱动的组织衰老和CLD的发现。 We will also include experiments that ask how acute neutrophilic inflammation associated with infections exacerbates NASH, this being relevant to Covid-19 which is reported to aggravate CLD.Secondly, we will ask if our discovery that neutrophils are attracted to senescent cells can be exploited to stimulate the immune system to clear senescent hepatocytes. We will engineer neutrophils to express antibodies at their surface that selectively lock onto proteins expressed at the surface of senescent cells, this aimed at enhancing their physical interaction and in doing so encouraging neutrophil-mediated clearance of senescent cells.By carrying out this 3-year project we will (1) substantially increase knowledge of how inflammation and ageing combine to promote CLD, (2) discover new mechanistic biology of broad interest to biologists and免疫学家和（3）学习中性粒细胞是否可以在与肥胖相关的疾病和肥胖相关疾病中的免疫治疗目的操纵。