What is inflammation? And what are we doing to stop it?
Inflammation is a key driver of many diseases. Our innate immune system – the body’s first line of defence – is particularly important in initiating inflammation, which is essential for eliminating agents that may cause harm and for healing, but if uncontrolled, it can cause enormous damage.
Researchers at the Centre for Inflammation and Disease Research at the Institute for Molecular Bioscience (IMB) are developing a detailed understanding of how inflammation works, so they can devise strategies to control it. If they can block or reduce inflammation when it is unchecked, they may be able to develop new approaches to tackle many important and common diseases.
Prolonged and/or dysregulated inflammatory responses can contribute to the initiation or progression of diseases such as cancer, metabolic diseases (diabetes types 1 and 2, liver disease, atherosclerosis and other cardiovascular diseases), autoimmune diseases (e.g. rheumatoid arthritis), and neurodegenerative diseases (e.g.
Alzheimer’s disease).
Here are some of the key research areas that IMB is progressing to stop inflammation.
The Inflammasome: sensing and responding to danger
The Inflammasome is a pathway that is active in our bodies within cells that is designed to sense and respond to danger. However, according to Professor Matt Sweet, Director of the Centre for Inflammation and Disease Research, these pathways can have harmful effects in addition to their protective roles.
“It does have a protective role in infection,
but in many inflammatory diseases it is driving inappropriate inflammation,” he says.
Associate Professor Kate Schroder’s lab is looking for ways to switch off the inflammasome using molecular and cell biology approaches, along with in vivo studies.
“There are different ‘flavours’ of inflammasomes. Each does different things and is activated by different things,” says Associate Professor Schroder.
“If we understand this cell signalling pathway we can determine how and where to block it. Depending on how far ‘upstream’ the pathway is blocked, we could block one or more of the inflammasomes to stop inappropriate inflammation.”
Toll–like Receptors: How cells talk during inflammation
Toll–like receptors turn on the production of cytokines that communicate with other cells to drive inflammation. Professor Sweet says these receptors are very important when we are young, but they can do more harm than good when we become adults.
“When we’re young we don’t tend to have a very well developed adaptive immune system – so we rely more on our innate immune system. But in adulthood, we can cope reasonably well against infectious diseases without Toll–like receptors. Triggering these receptors to act in older people can contribute to the progression of chronic diseases” Professor Sweet explains.
“We’re developing ways to manipulate these pathways. For example, we recently discovered a mechanism by which Toll–like receptors are controlled. We found that the SCIMP protein is required for Toll–like receptor–inducible production of certain cytokines, and so it fine–tunes inflammation. The discovery of this pathway has opened a new area of research in working out how cells talk to each other during inflammation and disease.”
Macrophages: the white blood cells kicking off inflammation
Professor Jennifer Stow’s laboratory is exploring how white blood cells called macrophages are activated and then how they turn off inflammatory responses.
Professor Stow says it is a natural process that ensures inflammation is only an acute temporary response.
“In disease, however, this control system is somehow overridden, which allows the process to keep going,” she says.
“By understanding how cells normally turn inflammation off, we can develop approaches to turn off this process in chronic disease.”
Cancer
Inflammation is a key process contributing to cancer development and metastasis.
For example, inflammation of the intestinal tract, if unchecked and chronic, can lead to inflammatory bowel disease and colon cancer. IMB researchers are examining new approaches to target inflammatory bowel disease.
Professor Stow says that the white blood cells involved in setting up inflammatory responses also contribute to cancer cell growth and evasion of the immune system.
“Inflammation can play a very complicated role in cancer. It can help to kill off cancer cells in the initial stages of tumour development, but then impact on our ability to fight off cancer by inadvertently helping cancers to metastasise.”
“We’re determining how to turn inflammation on and off at the right time in cancer.”
Chronic Liver Disease
Another disease associated with inflammation is chronic liver disease. There are many different causes of liver disease, including some viruses (Hepatitis B and Hepatitis C), as well as diet and lifestyle. But irrespective of how the disease is caused, inflammation is a key driver of the underlying pathology.
Professor Matt Sweet says that there are now effective treatments for Hepatitis C virus, and these can result in the regression of liver disease in infected patients. However, there are no approved treatments for non–alcoholic fatty liver disease (NAFLD), a syndrome that can progress to non–alcoholic steatohepatitis (NASH) and liver cirrhosis.
“The incidence of NAFLD in the general population is quite high and is continuing to rise, so this is going to be a massive problem in the future, and there is a serious unmet need.
“NAFLD affects around 6 million Australians and around 25% of the world’s population in some form, although many are not aware of it and have no obvious symptoms.”
The focus at the IMB is on trying to understand the disease. Researchers are trialling experimental treatments in mice, and are collaborating with clinicians with expertise in chronic liver disease to find patient gene signatures associated with disease progression.
“We’re looking for potential biomarkers, the proteins involved in driving the disease, which may also be new therapeutic targets.”