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

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.