Monika Bambouskova, PhD and collaborators had their research published March 9 in Cell Reports.
The authors state, “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 NLR family pyrin domain containing 3 (NLRP3) inflammasome activation after long lipopolysaccharide (LPS) priming, which establishes tolerance to late NLRP3 inflammasome activation. We show that itaconate acts synergistically with inducible nitric oxide synthase (iNOS) and that 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 that, if uncontrolled, can result in pyroptotic cell death and tissue damage.”
Itaconate confers tolerance to late NLRP3 inflammasome activation
Dr. Bambouskova’s research interests are in the specific metabolic requirements of immune cells that provide novel promising targets of therapeutic intervention to modulate inflammatory diseases. Dr. Bambouskova studies how metabolic regulation integrates with immune cell signaling. During her postdoctoral work she focused on metabolic rewiring in activating macrophages, particularly on the role of metabolite itaconate in regulation of macrophage inflammatory response. Her work defined a fundamentally novel connection between the cellular stress response and IκBζ-mediated inflammatory axis and its therapeutic impact for number of autoimmune diseases. Her ongoing research program employs molecular biology and biochemistry techniques together with systems approaches to tackle molecular mechanisms of crosstalk between metabolism and cell signaling in the regulation of immune responses.
Monika Bambouskova, Lucie Potuckova, Tomas Paulenda, Martina Kerndl, Denis A. Mogilenko, Kate Lizotte, Amanda Swain, Sebastian Hayes, Ryan D. Sheldon, Hyeryun Kim, Unnati Kapadnis, Abigail E. Ellis, Christine Isaguirre, Samantha Burdess, Anwesha Laha, Gaya K. Amarasinghe, Victor Chubukov, Thomas P. Roddy, Michael S. Diamond, Russell G. Jones, Donald M. Simons, Maxim N. Artyomov. Itaconate confers tolerance to late NLRP3 inflammasome activation. Cell Reports, March 9, 2021