The role of cell death in a rare autoimmune disease

An international team of scientists has shown for the first time the important and different role played by the proteins MLKL and RIPK3 as regulators of the necroptotic process in a preclinical model of autoimmune disease. Their research has been published in the journal Immunity.

Lead researcher Dr Silvia Alvarez-Diaz, from Melbourne’s Walter and Eliza Hall Institute, explained that necroptosis is a form of regulated necrosis, or harmful cell death. She said the process has “gained increased interest in the scientific community because of its implication in several diseases — mainly severe inflammatory conditions, including pancreatitis or inflammatory bowel disease and possibly in cancer development”.

As RIPK3 and MLKL both play a vital role controlling the death of cells by necroptosis, a lot of research is currently being done to develop inhibitors of these molecules to be used in the clinic. “Blocking RIPK3 or MLKL stops cells from dying by necroptosis and can be useful for the treatment of inflammatory diseases or even cancer,” noted Dr Alvarez-Diaz.

However, RIPK3 can also contribute to apoptosis — another form of programmed cell death — and to the production of cytokines — molecules that induce inflammation. Dr Alvarez-Diaz said this must be taken into account when developing new therapies that target necroptosis.

“We need to know how differently these two molecules behave in a similar context in order to know which one is the best target for a new drug, including what the possible side effects of targeting either of these proteins may be,” she said.

Dr Alvarez-Diaz and her research team have now compared the effect of blocking the activity of either RIPK3 or MLKL in a preclinical model of autoimmune lymphoproliferative syndrome (ALPS) — a rare genetic disorder in which the processes that control cell death do not work correctly — for the first time. People with ALPS develop autoimmune disorders have an increased risk of developing cancers of white blood cells.

Dr Alvarez-Diaz revealed that “while MLKL has no major effects, RIPK3 worsens the development and progression of this disease, mainly due to the non-necroptotic functions of RIPK3”. By developing further understanding of how differently these molecules work, she added, “we could develop new drugs that activate or deactivate the pathway and could be used for the treatment of a range of human diseases”.