Itaconate confers tolerance to late NLRP3 inflammasome activation

Itaconate confers tolerance to late NLRP3 inflammasome activation

Abstract Itaconate is a unique regulatory metabolite that is induced upon toll-like receptor (TLR) stimulation in myeloid cells. Here, we demonstrate major inflammatory tolerance and cell death phenotypes associated with itaconate production in activated macrophages. We show that endogenous itaconat...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2021-05, Vol.206 (1_Supplement), p.15-15.11
Main Authors: Bambouskova, Monika, Potuckova, Lucie, Paulenda, Tomas, Kerndl, Martina, Mogilenko, Denis A., Lizotte, Kate, Swain, Amanda, Hayes, Sebastian, Sheldon, Ryan D., Kim, Hyeryun, Kapadnis, Unnati, Ellis, Abigail E., Isaguirre, Christine, Burdess, Samantha, Laha, Anwesha, Amarasinghe, Gaya K., Chubukov, Victor, Roddy, Thomas P., Diamond, Michael S., Jones, Russell J., Simons, Donald M., Artyomov, Maxim N.
Format: Article
Language:eng
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Summary:Abstract Itaconate is a unique regulatory metabolite that is induced upon toll-like receptor (TLR) stimulation in myeloid cells. Here, we demonstrate major inflammatory tolerance and cell death phenotypes associated with itaconate production in activated macrophages. We show that endogenous itaconate is a key regulator of the signal 2 of NLRP3 inflammasome activation after long LPS priming which establishes tolerance to late NLRP3 inflammasome activation. We show that itaconate acts synergistically with iNOS and the ability of various TLR ligands to establish NLRP3 inflammasome tolerance depends on the pattern of co-expression of IRG1 and iNOS. Mechanistically, itaconate accumulation upon prolonged inflammatory stimulation prevents full caspase-1 activation and processing of gasdermin D, which we demonstrate to be post-translationally modified by endogenous itaconate. Altogether, our data demonstrate that metabolic rewiring in inflammatory macrophages establishes tolerance to NLRP3 inflammasome activation which, if uncontrolled, can result in pyroptotic cell death and tissue damage.
ISSN:0022-1767
1550-6606