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Itaconate Negatively Regulates Innate Signaling through Modification of IRAK4, Degradation of NFκB, and the Modulation of Global Ubiquitination

ABSTRACT: A wide variety of electrophilic derivatives of the Kreb’s cycle-derived metabolite, itaconate, 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 NFκB, and modulates global ubiquitination patterns. As a result, cells unable to make itaconate overproduce inflammatory cytokines such as TNFα, IL6, and IL-1β in response to these innate activators. In contrast, the production of IFNβ, 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.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Frank C. Dorsey

PROVIDER: PXD053956 | JPOST Repository | Tue Jul 16 00:00:00 BST 2024

REPOSITORIES: jPOST

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			Action	DRS
	THP1_IRG1_KO_0hr_A1.raw	Raw
	THP1_IRG1_KO_0hr_A2.raw	Raw
	THP1_IRG1_KO_0hr_B1.raw	Raw
	THP1_IRG1_KO_0hr_B2.raw	Raw
	THP1_IRG1_KO_24hr_A1.raw	Raw

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Itaconate Negatively Regulates Innate Signaling through Modification of IRAK4, Degradation of NFκB, and the Modulation of Global Ubiquitination

Project description:A wide variety of electrophilic derivatives of the Kreb’s cycle-derived metabolite, itaconate, 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 NFκB, and modulates global ubiquitination patterns. As a result, cells unable to make itaconate overproduce inflammatory cytokines such as TNFα, IL6, and IL-1β in response to these innate activators. In contrast, the production of IFNβ, 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.

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Difference of gene expression between LPS-stimulated monocytes cultured in the presence NRBCs and those cultured in the absence of NRBCs

Project description:We found that human cord blood nucleated red blood cells (NRBCs) have a regulatory function in the innate immune reaction. NRBCs suppressed the production of inflammatory cytokines including TNF-a and IL-1b from monocytes in response to lipopolysaccharide (LPS). NRBCs exerted the regulatory function even without cell-to-cell contact with monocytes. On the other hand, IL-10 production from monocytes by the stimulation of LPS in the presence of NRBCs was higher than that of LPS-stimulated monocytes cultured in the absence of NRBCs. Addition of an anti-IL-10 receptor blocking antibody restored the inflammatory cytokine production from monocytes, suggesting that the functional change of monocytes caused by the interaction of NRBCs was characterized and mediated by the increased IL-10 production. Whole-genome microarray analysis revealed that monocytes expressed increased amounts of IL-10 superfamily genes after the interaction with NRBCs. IL-19, one of the IL-10 superfamily, enhanced IL-10 production from monocytes, which suggested cooperative role of IL-10 superfamily in the suppression of inflammatory cytokine production from monocytes. Arginase which was reported to play an important role in the suppressive function of NRBCs on monocytes in mice was found to play no significant role in human monocytes. NRBCs seem to have a regulatory role to suppress vigorous innate immune reaction which can be harmful to the fetuses via some unknown soluble factor which enhances the production of IL-10 and IL-10 family cytokines in monocytes. Human LPS-stimulated monocytes were collected after culture in a condition without and with NRBCs in transwell culture system. Only one experiment was performed.

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Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation

Project description:Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation mechanism accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the downstream pro-inflammatory IL-1Î²-HIF1a axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions via its effect on succinate dehydrogenase, by inhibiting conversion of succinate to fumarate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1-/- mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, changes in mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages. Experiment 1: mature WT BMDM were treated for 12h with 0.25 mM dimethyl itaconate (DI) or vehicle (Unst) and then stimulated with LPS (E. coli 0111:B4; 100 ng/ml, 4h) (DI+LPS; LPS); Experiment 2: mature Irg1-/- BMDM were stimulated with LPS (E. coli 0111:B4; 100 ng/ml) and murine recombinant IFNg (50 ng/ml) for 24h.

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2012-04-03 | E-GEOD-30840 | biostudies-arrayexpress

Transcription profiling of spleens from dual specificity phosphatase-1 (DUSP1) deficient and wild type mice to demonstrate a specific regulatory role of DUSP1 on a subset of LPS-induced genes that control the outcome of endotoxin shock.

Project description:Activation of the Mitogen activated protein kinase (MAPK) cascade following Toll-like receptor (TLR) stimulation enables innate immune cells to rapidly activate cytokine gene expression. A balanced response to signals of infectious danger requires that cellular activation is transient. Here, we identify the MAPK phosphatase Dual specificity phosphatase-1 (DUSP1) as an essential endogenous regulator of the inflammatory response to LPS. DUSP1-deficient (DUSP1-/-) bone marrow derived macrophages showed selectively prolonged activation of p38 MAPK and increased cytokine production. Intraperitoneal challenge of DUSP1-/- mice with LPS caused increased lethality and overshooting production of IL-6 and TNF. Transcriptional profiling revealed that DUSP1 controls a significant fraction of LPS-induced genes, that includes IL-6 and IL-10 as well as the chemokines CCL3, CCL4 and CXCL2. In contrast, the expression of the important mediators of endotoxin lethality, IFN? and IL-12, was not significantly altered by the absence of DUSP1. These data together demonstrate a specific regulatory role of DUSP1 in controlling a subset of LPS-induced genes that determines the outcome of endotoxin shock. Experiment Overall Design: Mice were injected intraperitoneally with E. coli LPS (10µg/g bodyweight) and sacrificed 6h later. Total spleen RNA (5 µg) was prepared, labeled and hybridized to Affymetrix MOE430A 2.0 GeneChips according to the manufacturer's instructions. Three biological replicates per condition were analysed. CEL Files were processed for global normalization and generation of expression values using the rma algorithm in the R affy package (www.bioconductor.org).

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Difference of gene expression between LPS-stimulated monocytes cultured in the presence NRBCs and those cultured in the absence of NRBCs

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Control of LPS-response by DUSP1

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