Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1

By E. Mills, D. Ryan, H. Prag, D. Dikovskaya, D. Menon, Z. Zaslona, Mark P. Jedrychowski, Ana S. H. Costa, M. Higgins, E. Hams and 25 more. Nature, 2018

1,634 citations recorded by the source corpus.

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

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/bcfc701209a7f2da98bdaf4aba33acb4f2f3de91

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. F. Munari
2. R. Sánchez-Rodríguez
3. Tommaso Scolaro
4. A. Viola
5. Alessandra Castegna

In Molecular Biology

1. Ping Gao
2. Huafeng Zhang
3. E. Panieri
4. L. Saso
5. Linchong Sun

Citations in the corpus

• The Metabolic Signature of Macrophage Responses (2019, background): “: itaconate contributes to stabilize the levels of the anti-inflammatory transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), which targets genes involved in anti-inflammatory and anti-oxidant response (97).”
• An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation (2020, background): “Several cell-derived metabolites such as itaconate and fumarate demonstrated anti-inflammatory responses in LPS- stimulated macrophages [237].”
• Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “…mainly by stimulated macrophages, can modify protein alkylation and protein itaconation (Lampropoulou et al., 2016; Bambouskova et al., 2018; Mills et al., 2018; Qin et al., 2019; Qin et al., 2020), but it is unclear whether it directly modifies histones or indirectly modify histones…”