Off-switch for inflammation discovered!

Off-switch for inflammation discovered!


Scientists have discovered a new metabolic process in the body that can switch off inflammation. They have discovered that 'itaconate' - a molecule derived from glucose - acts as a powerful off-switch for macrophages, which are the cells in the immune system that lie at the heart of many inflammatory diseases including arthritis, inflammatory bowel disease and heart disease.

Senior author said: "My lab has been exploring metabolic changes in macrophages for the past six years and we've come across what we think is the most important finding yet."

"It is well known that macrophages cause inflammation, but we have just found that they can be coaxed to make a biochemical called itaconate. This functions as an important brake, or off-switch, on the macrophage, cooling the heat of inflammation in a process never before described."

A joint first author of the work, said: "The macrophage takes the nutrient glucose, whose day job it is to provide energy, and surprisingly turns it into itaconate. This then blocks production of inflammatory factors, and also protects mice from the lethal inflammation that can occur during infection."

Another author added: "We've found that itaconate can directly modify a whole host of proteins important for inflammation in a chemical reaction never before described, and that this reaction is important for the anti-inflammatory effects of itaconate."

Authors show that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 (also known as NFE2L2) by lipopolysaccharide in mouse and human macrophages. They find that itaconate directly modifies proteins via alkylation of cysteine residues. Itaconate alkylates cysteine residues 151, 257, 288, 273 and 297 on the protein KEAP1, enabling Nrf2 to increase the expression of downstream genes with anti-oxidant and anti-inflammatory capacities. The activation of Nrf2 is required for the anti-inflammatory action of itaconate.

Researchers describe the use of a new cell-permeable itaconate derivative, 4-octyl itaconate, which is protective against lipopolysaccharide-induced lethality in vivo and decreases cytokine production. They show that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconate production. Furthermore, authiors find that itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate. 

The discovery is very much on the frontier of inflammation research and the researchers are now exploring its relevance to the onset and development of inflammatory and infectious diseases. They are also keen to explore whether the findings can be exploited in the effort to develop new anti-inflammatory medicines.

http://www.tcd.ie/news_events/articles/scientists-discover-promising-off-switch-for-inflammation/8729

https://www.nature.com/articles/nature25986

Edited

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