Periodic Reporting for period 1 - ReKUPFFERate (Investigating if recuperating hepatic macrophage numbers and functions in chronic fibrosis can limit the incidence and severity of infections)
Okres sprawozdawczy: 2023-10-01 do 2025-09-30
Liver damage, caused by fibrosis, is the 14th most common cause of death in adults worldwide. In addition to this, it is a major risk factor for infections, where patients with chronic liver fibrosis (cirrhosis) are more likely to acquire infections, and to die from these infections in hospitals, when compared to other patients. As such, this poses a major health burden in Europe and the wider world. The healthy liver is full of immune cells which sit in the bloodstream and constantly survey for damage and infections. One of the cells most suited for this role are the liver resident macrophages. During fibrosis we know that these resident cells are lost and replaced by diverse populations of inflammatory macrophages. We believe that this plays a role in the increased susceptibility to infections in cirrhotic patients. Therefore, in this work this project aimed to understand the following:
Identify changes occurring in the immune cells in the fibrotic liver
Find genes which can become therapeutic targets in the immune cells
Improve the response to infections in cirrhosis via these targets
Taken together, this work aimed to improve the understanding of the role of macrophages in the liver during cirrhosis and infections. This was in order to improve the response in patients and lessen the health burden worldwide, both from chronic liver disease and from sepsis, the inappropriate and severe response to infection. This could improve the treatment and detection of infections within cirrhotic patients, leading to new avenues of research and potential targetable mechanisms.
Identify changes occurring in the immune cells in the fibrotic liver
Find genes which can become therapeutic targets in the immune cells
Improve the response to infections in cirrhosis via these targets
Taken together, this work aimed to improve the understanding of the role of macrophages in the liver during cirrhosis and infections. This was in order to improve the response in patients and lessen the health burden worldwide, both from chronic liver disease and from sepsis, the inappropriate and severe response to infection. This could improve the treatment and detection of infections within cirrhotic patients, leading to new avenues of research and potential targetable mechanisms.
In order to address these public health issues, established preclinical models of liver fibrosis were used in combination with several different types of bacteria or molecules mimicking infection signals. This project was able to establish that infections or similar inflammatory stimulation was able to delay the resolution of fibrosis. A data set showing the evolving immune cell response to Salmonella in the context of fibrosis was also generated. This data was then translated into potential gene targets, which appeared to be driving a change within macrophage populations within the context of infections. This represents a new resource in the soon to be publicly accessible dataset (will be made available upon publication of the results), and a better understanding of the dynamics of immune cell responses to infections in the liver in the context of fibrosis. This will aid the scientific community to tackle these problems in a data driven manner.
This work is among the first to link several different infection models to a newly discovered liver macrophage specific effect. This project uncovered a new genetic target which is a key driver of this effect. It also generated several data sets which can be used by other researchers upon publication to better understand immune cells during infections and fibrosis. This work will be useful to other researchers and medical professionals trying to understand how the mechanisms of the immune system fail to respond to infections in cirrhotic patients. These discoveries lay the foundation for new targets which can be built upon, by further dissecting these mechanisms in detail. This may allow the exploitation of these systems to develop potential inhibitors, or to stimulate greater immune responses in patients. This would help to tackle the large health burden and suffering caused by chronic liver disease and sepsis.