Scientists discover promising ‘off-switch’ for inflammatory diseases

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A critical finding was to show itaconate switched off an over-active immune system in mice.

“It’s well known that macrophages cause inflammation, but we have just found 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,” Prof O’Neill said.

Itaconate
Dr Evanna Mills, who with PhD student Dylan Ryan is the 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.”"

interesting
 
From the article:

Teams led by immunologist Prof Luke O’Neill, who is based in Trinity, and Dr Mike Murphy, of the University of Cambridge, have discovered that “itaconate” – a molecule derived from glucose – “acts as a powerful off switch for macrophages”, which are cells operating at the heart of the the immune system where inflammation occurs.
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Paper the article is based on is in Nature this week. Note that the research was done on mice:

Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1 Evanna L. Mills et al.

Abstract
The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood1,2,3.

Here we 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. We 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. We 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.

We show that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconate production. Furthermore, we find that itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate.

Our findings demonstrate that itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and modulate type I interferons
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https://www.nature.com/articles/nature25986
 
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