Endogenously produced itaconate negatively regulates innate-driven cytokine production and drives global ubiquitination in human macrophages.

Autor:	Bourner LA; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA., Chung LA; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA., Long H; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA., McGettrick AF; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, D02 PN40 Dublin, Ireland., Xiao J; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA., Roth K; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA., Bailey JD; Sitryx Therapeutics Limited, Bellhouse Building, Magdalen Centre, The Oxford Science Park, Oxford OX4 4GA, UK., Strickland M; Sitryx Therapeutics Limited, Bellhouse Building, Magdalen Centre, The Oxford Science Park, Oxford OX4 4GA, UK., Tan B; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA., Cunningham J; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA., Lutzke B; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA., McGee J; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA., Otero FJ; Eli Lilly and Company, Lilly Biotechnology Center, San Diego, CA 92121, USA., Gemperline DC; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA., Zhang L; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA., Wang YC; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA., Chalmers MJ; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA., Yang CW; Eli Lilly and Company, Lilly Biotechnology Center, San Diego, CA 92121, USA., Gutierrez JA; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA., O'Neill LAJ; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, D02 PN40 Dublin, Ireland., Dorsey FC; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: fdorsey@lilly.com.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Aug 27; Vol. 43 (8), pp. 114570. Date of Electronic Publication: 2024 Aug 01.
DOI:	10.1016/j.celrep.2024.114570
Abstrakt:	A wide variety of electrophilic derivatives of itaconate, the Kreb's cycle-derived metabolite, are immunomodulatory, yet these derivatives have overlapping and sometimes contradictory activities. Therefore, we generated a genetic system to interrogate the immunomodulatory functions of endogenously produced itaconate in human macrophages. Endogenous itaconate is driven by multiple innate signals restraining inflammatory cytokine production. Endogenous itaconate directly targets cysteine 13 in IRAK4 (disrupting IRAK4 autophosphorylation and activation), drives the degradation of nuclear factor κB, and modulates global ubiquitination patterns. As a result, cells unable to make itaconate overproduce inflammatory cytokines such as tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and IL-1β in response to these innate activators. In contrast, the production of interferon (IFN)β, downstream of LPS, requires the production of itaconate. These data demonstrate that itaconate is a critical arbiter of inflammatory cytokine production downstream of multiple innate signaling pathways, laying the groundwork for the development of itaconate mimetics for the treatment of autoimmunity. Competing Interests: Declaration of interests L.A.B., L.A.C., H.L., J.X., K.R., B.T., F.J.O., D.C.G., L.Z., Y.C.W., M.J.C., C.-W.Y., J.A.G., and F.C.D. are employees and shareholders of Eli Lilly and Company. L.A.J.O., M.S., and J.D.B. are employees or shareholders of Sitryx. (Copyright © 2024 Eli Lilly and Company. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu