Link found between cell death and inflammatory disease

May 12, 2014 by Liz Williams
Link found between cell death and inflammatory disease
Mr James Rickard, Mr Joseph Evans and Ms Joanne O'Donnell (L-R) were part of an institute team that showed cell death by necroptosis could be the underlying cause of inflammatory disease.

(Medical Xpress)—A team of Melbourne researchers has shown a recently discovered type of cell death called necroptosis could be the underlying cause of inflammatory disease.

The research team discovered that a previously identified molecule involved in necroptosis, called RIPK1, was essential for survival by preventing uncontrolled inflammation. This finding could lead to future treatments for including Crohn's disease, and psoriasis.

The researchers, from the Walter and Eliza Hall Institute, also discovered that the 'survival' molecule RIPK1 acts as the 'gatekeeper' between cell life and death. In a paper published in the journal Cell, they reveal RIPK1 is essential for a cell's decision to live or die, and in choosing how to die.

Institute researchers Associate Professor John Silke from the Cell Signalling and Cell Death division, Dr Motti Gerlic from the Inflammation division and Dr Ben Croker led the project, working with PhD students Mr James Richard, Ms Joanne O'Donnell and Mr Joseph Evans. Associate Professor Silke said the team had shown for the first time that RIPK1 (receptor interacting protein kinase 1) was a master controller of cell life and death.

"We showed that, in the body, RIPK1 is not only essential for initiating necroptosis, but also for inhibiting necroptosis and the runaway inflammation that can cause severe tissue damage," Associate Professor Silke said. "We also found that it played a role in another type of programmed called apoptosis. Our research highlighted that RIPK1 is the gatekeeper that controls whether a cell lives or dies, and the decision it makes on how to die."

Necroptosis is a type of 'controlled' death that instructs a cell to die while stimulating an inflammatory reaction to let the immune system know something has gone wrong. However when this cell death pathway begins to spiral out of control, it can lead to inflammatory disease. Necroptosis has also been implicated in neurodegenerative disease, brain injuries caused by blood loss, and some viral infections.

Dr Gerlic said their study provided the first evidence that RIPK1 was essential for inhibiting necroptosis. "This research puts a new dogma on the table about RIPK1 and its role in controlling or inhibiting necroptosis," Dr Gerlic said. "It is also the first time that we have shown necroptosis and the molecules involved actually induce inflammatory disease, suggesting that targeting this pathway could be useful for treating human conditions such as psoriasis, rheumatoid arthritis and Crohn's disease."

Associate Professor Silke said necroptosis was a newly discovered type of cell death that had only really been studied in the past five years. "When our time comes to die, we don't have a choice," he said. "However cells make this choice all the time – not only whether they die, but also how they die. They can choose to die quietly, or they can make a fuss. Necroptosis is their way of letting everyone else know that they are dying and help is needed usually when something has gone wrong such as a viral infection."

Dr Gerlic said the research team had also shown RIPK1 played other important roles in the body. "As part of the research we found that RIPK1 was essential for keeping blood stem cells alive after bone marrow transplant," he said. "This finding is particularly important when considering treatments that target RIPK1, as it could have unwanted side-effects for other cells in the body. Therefore it is important to ensure any potential drugs are properly investigated for any off-target effects."

Associate Professor Silke said the institute was already capitalising on its expertise in necroptotic cell death with a drug discovery program to identify small molecules that could target molecules downstream of RIPK1 in the necroptotic pathway, such as MLKL (mixed lineage kinase domain-like).

Explore further: Cell death protein could offer new anti-inflammatory drug target

Related Stories

Cell death protein could offer new anti-inflammatory drug target

September 5, 2013
Scientists in Melbourne, Australia, have revealed the structure of a protein that is essential for triggering a form of programmed cell death, making possible the development of new drugs to treat chronic inflammatory diseases ...

Controlling cell death prevents skin inflammation

October 13, 2011
The outer layer of the skin, called the epidermis, forms a critical physical and immunological wall that serves as the body's first line of defense against potentially harmful microorganisms. Most of the epidermis consists ...

Scientists identify cell death pathway involved in lethal sepsis

December 22, 2011
Sepsis, a form of systemic inflammation, is the leading cause of death in critically ill patients. Sepsis is linked with massive cell death; however, the specific mechanisms involved in the lethality of sepsis are unclear. ...

Liver cancer due to chronic inflammation: Tumour growth follows programmed cell death (apoptosis)

August 30, 2013
The death of numerous liver cells in the context of chronic inflammation due to apoptosis, a form of programmed cell death, can promote the formation of tumour cells in the liver. This insight significantly contributes to ...

Necrostatin-1 counteracts aluminum's neurotoxic effects

August 5, 2013
Investigators have linked aluminum accumulation in the brain as a possible contributing factor to neurodegenerative disorders such as Alzheimer's disease. A new study published in Restorative Neurology and Neuroscience sheds ...

Immune system kill switch could be target for chemotherapy and infection recovery

December 6, 2012
Researchers have discovered an immune system 'kill switch' that destroys blood stem cells when the body is under severe stress, such as that induced by chemotherapy and systemic infections.

Recommended for you

New insights into protein's role in inflammatory response

July 28, 2017
A protein called POP2 inhibits a key inflammatory pathway, calming the body's inflammatory response before it can become destructive, Northwestern Medicine scientists have demonstrated in mouse models.

Targeting 'broken' metabolism in immune cells reduces inflammatory disease

July 12, 2017
The team, led by researchers at Imperial College London, Queen Mary University of London and Ergon Pharmaceuticals, believes the approach could offer new hope in the treatment of inflammatory conditions like arthritis, autoimmune ...

A perturbed skin microbiome can be 'contagious' and promote inflammation, study finds

June 29, 2017
Even in healthy individuals, the skin plays host to a menagerie of bacteria, fungi and viruses. Growing scientific evidence suggests that this lively community, collectively known as the skin microbiome, serves an important ...

Inflammatory bowel disease: Scientists zoom in on genetic culprits

June 28, 2017
Scientists have closed in on specific genes responsible for Inflammatory Bowel Disease (IBD) from a list of over 600 genes that were suspects for the disease. The team from the Wellcome Trust Sanger Institute and their collaborators ...

Trials show unique stem cells a potential asthma treatment

June 28, 2017
A study led by scientists at Monash University has shown that a new therapy developed through stem cell technology holds promise as a treatment for chronic asthma.

Researchers find piece in inflammatory disease puzzle

May 23, 2017
Inflammation is the process by which the body responds to injury or infection but when this process becomes out of control it can cause disease. Monash Biomedicine Discovery Institute (BDI) researchers, in collaboration with ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.