Itaconate confers tolerance to late NLRP3 inflammasome activation
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
Affiliations
Monika Bambouskova
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Lucie Potuckova
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Tomas Paulenda
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Martina Kerndl
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, 1090 Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, 1090 Vienna, Austria
Denis A. Mogilenko
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Kate Lizotte
Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA
Amanda Swain
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Sebastian Hayes
Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA
Ryan D. Sheldon
Van Andel Research Institute, Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Grand Rapids, MI 49503, USA
Hyeryun Kim
Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA
Unnati Kapadnis
Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA
Abigail E. Ellis
Van Andel Research Institute, Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Grand Rapids, MI 49503, USA
Christine Isaguirre
Van Andel Research Institute, Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Grand Rapids, MI 49503, USA
Samantha Burdess
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Anwesha Laha
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Gaya K. Amarasinghe
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Victor Chubukov
Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA
Thomas P. Roddy
Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA
Michael S. Diamond
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA
Russell G. Jones
Van Andel Research Institute, Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Grand Rapids, MI 49503, USA
Donald M. Simons
Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA
Maxim N. Artyomov
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Corresponding author
Summary: 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.
