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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

PROVIDER: GSE272396 | GEO | 2024/07/17

REPOSITORIES: GEO

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Project description:Exciting discoveries related to IL-1R/TLR signaling in development of atherosclerosis plaque have triggered intense interest in the molecular mechanisms by which innate immune signaling modulates the onset and development of atherosclerosis. Previous studies have clearly shown the definitive role of proinflammatory cytokine IL-1 in the development of atherosclerosis. Recent studies have provided direct evidence supporting a link between innate immunity and atherogenesis. While it is still controversial about whether infectious pathogens contribute to cardiovascular diseases, direct genetic evidence indicates the importance of IL-1R/TLR signaling in atherogenesis. In this study, we examined the role of IRAK4 kinase activity in modified LDL-mediated signaling using bone marrow-derived macrophage as well as in vivo model of atherosclerosis. First, we found that the IRAK4 kinase activity was required for modified LDL-induced NFÎºB activation and expression of a subset of proinflammatory genes, but not for the activation of MAPKs in bonemarrow-derived macrophage. IRAK4 kinase inactive knock-in (IRAK4KI) mice were bred onto ApoE-/- mice to generate IRAK4KI/ApoE-/- mice. Importantly, the aortic sinus lesion formation was impaired in IRAK4KI/ApoE-/- mice compared to that in ApoE-/- mice. Furthermore, proinflammatory cytokine production was reduced in the aortic sinus region of IRAK4KI/ApoE-/- mice compared to that in ApoE-/- mice. Taken together, our results indicate that the IRAK4 kinase plays an important role in modified LDL-mediated signaling and the development of atherosclerosis, suggesting that pharmacological inhibition of IRAK4 kinase activity might be a feasible approach in the development of anti-atherosclerosis drugs. To identify global changes in gene expression, we examined gene expression profiles of macrophages from wild-type and IRAK4 kinase-inactive knock-in mice in response to acLDL stimulation using the Illumina microarray with probes for 23,000 transcripts. Bone marrow-derived macrophages from wild-type and IRAK4 kinase-inactive knock-in mice were treated with acLDL for 24 hours.

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

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