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

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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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.

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