IL-1 induces mitochondrial translocation of IRAK2 to suppress oxidative metabolism in adipocytes

Zhou, Hao; Wang, Han; Yu, Michael C.; Schugar, Rebecca C.; Wen, Qian; Tang, Fangqiang; Liu, Weiwei; Yang, Hui; McDowell, Ruth E.; Zhao, Junjie; Gao, Ji; Dongre, Ashok; Carman, Julie A.; Yin, Mei; Drazba, Judith A.; Dent, Robert; Hine, Christopher; Chen, Yeong‐Renn; Smith, Jonathan; Fox, Paul L.; Brown, J. Mark; Li, Xiaoxia

doi:10.1038/s41590-020-0750-1

Cited by 36 publications

(41 citation statements)

References 58 publications

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“…Pregnancies resulting in a child with ASD have demonstrated increases in proinflammatory cytokines IL-1α [ 41 ] and IL-6 [ 41 ] in blood, while maternal elevation in IL-17a has been strongly implicated in the MIA model [ 42 ]. In laboratory studies, IL-17 [ 43 , 44 ] induces mitochondrial dysfunction through activation of the mitochondria-induced apoptosis pathway and IL-1 suppresses mitochondrial function [ 45 ], while IL-6 promotes mitochondrial biogenesis and fatty acid oxidation [ 46 ].…”

Section: Prenatal Risk Factors For Asd Modulate Mitochondrial Funcmentioning

confidence: 99%

Mitochondria May Mediate Prenatal Environmental Influences in Autism Spectrum Disorder

Frye

Cakir

Rose

et al. 2021

JPM

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We propose that the mitochondrion, an essential cellular organelle, mediates the long-term prenatal environmental effects of disease in autism spectrum disorder (ASD). Many prenatal environmental factors which increase the risk of developing ASD influence mitochondria physiology, including toxicant exposures, immune activation, and nutritional factors. Unique types of mitochondrial dysfunction have been associated with ASD and recent studies have linked prenatal environmental exposures to long-term changes in mitochondrial physiology in children with ASD. A better understanding of the role of the mitochondria in the etiology of ASD can lead to targeted therapeutics and strategies to potentially prevent the development of ASD.

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Section: Prenatal Risk Factors For Asd Modulate Mitochondrial Funcmentioning

confidence: 99%

Mitochondria May Mediate Prenatal Environmental Influences in Autism Spectrum Disorder

Frye

Cakir

Rose

et al. 2021

JPM

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“…However, MyD88, IRAK4, IRAK1, TAK1, and IkBa were not detected in mitochondrial fractions (62). In primary mouse adipocytes MyD88, IRAK4 and IRAK2, but not IRAK1, translocate to mitochondria upon IL-1b stimulation (63). In human macrophages we detected TRAF6, IRAK1 and IRAK4 in the mitochondrial fraction of unstimulated macrophages, and stimulation with zymosan did not alter their levels.…”

Section: Discussionmentioning

confidence: 66%

“…These findings demonstrate that MFN2 silencing may increase signal transduction via increased IRAK4 expression without affecting its activation. Cytosolic proteins that interact transiently with TLR signaling complexes can translocate to mitochondria, as shown for TRAF6 (62), MyD88, IRAK4, and IRAK2 (63). We hypothesized that in our system similar translocations can take place.…”

Section: Mfn2 Deficiency Enhances Macrophage Pro-inflammatory Responses To Zymosanmentioning

confidence: 81%

“…West et al demonstrated that TLR1, TLR2, and TLR4 are involved in the recruitment of mitochondria to phagosomes in murine RAW 264.7 macrophages (62). Cytosolic proteins can interact with TLR signaling complexes and translocate to mitochondria (62,63). For example, TRAF6 relocates to mitochondria where it ubiquitinates evolutionarily conserved signaling intermediate in Toll pathways protein, resulting in elevated levels of mitochondrial and cellular ROS (62).…”

Section: Discussionmentioning

confidence: 99%

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Mitofusin 2 Deficiency Causes Pro-Inflammatory Effects in Human Primary Macrophages

et al. 2021

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Mitofusin 2 (MFN2) is a mitochondrial outer membrane GTPase, which modulates mitochondrial fusion and affects the interaction between endoplasmic reticulum and mitochondria. Here, we explored how MFN2 influences mitochondrial functions and inflammatory responses towards zymosan in primary human macrophages. A knockdown of MFN2 by small interfering RNA decreased mitochondrial respiration without attenuating mitochondrial membrane potential and reduced interactions between endoplasmic reticulum and mitochondria. A MFN2 deficiency potentiated zymosan-elicited inflammatory responses of human primary macrophages, such as expression and secretion of pro-inflammatory cytokines interleukin-1β, -6, -8 and tumor necrosis factor α, as well as induction of cyclooxygenase 2 and prostaglandin E2 synthesis. MFN2 silencing also increased zymosan-induced nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen-activated protein kinases inflammatory signal transduction, without affecting mitochondrial reactive oxygen species production. Mechanistic studies revealed that MFN2 deficiency enhanced the toll-like receptor 2-dependent branch of zymosan-triggered responses upstream of inhibitor of κB kinase. This was associated with elevated, cytosolic expression of interleukin-1 receptor-associated kinase 4 in MFN2-deficient cells. Our data suggest pro-inflammatory effects of MFN2 deficiency in human macrophages.

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“…Among these, 776 were upregulated and 199 were downregulated in patients with AR compared to patients with non-AR. The volcano plots showed differences in PBMC gene expression between AR and non-AR (Figure 1A), and only the top 20 significantly expressed genes are shown in Figure, including several important genes, such as C1QC, VEGFA, IRAK2, HIF1A, and SERPINE1, which are closely associated with the immune system, growth of peripheral blood vessels, suppression of oxidative phosphorylation and fatty acid oxidation, and systemic insulin resistance (19)(20)(21)(22). A total of 1,036 genes were identified as DEGs distinguishing the PBMCs of patients with ABMR from those of non-AR individuals, among which 730 were upregulated and 306 were downregulated (Figure 2A).…”

Section: Rna-seq and Differential Gene Expression Analysismentioning

confidence: 99%

Pre-transplant Transcriptional Signature in Peripheral Blood Mononuclear Cells of Acute Renal Allograft Rejection

et al. 2022

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Acute rejection (AR) is closely associated with renal allograft dysfunction. Here, we utilised RNA sequencing (RNA-Seq) and bioinformatic methods to characterise the peripheral blood mononuclear cells (PBMCs) of patients with acute renal allograft rejection. Pretransplant blood samples were collected from 32 kidney allograft donors and 42 corresponding recipients with biopsies classified as T cell-mediated rejection (TCMR, n = 18), antibody-mediated rejection (ABMR, n = 5), and normal/non-specific changes (non-AR, n = 19). The patients with TCMR and ABMR were assigned to the AR group, and the patients with normal/non-specific changes (n = 19) were assigned to the non-AR group. We analysed RNA-Seq data for identifying differentially expressed genes (DEGs), and then gene ontology (GO) analysis, Reactome, and ingenuity pathway analysis (IPA), protein—protein interaction (PPI) network, and cell-type enrichment analysis were utilised for bioinformatics analysis. We identified DEGs in the PBMCs of the non-AR group when compared with the AR, ABMR, and TCMR groups. Pathway and GO analysis showed significant inflammatory responses, complement activation, interleukin-10 (IL-10) signalling pathways, classical antibody-mediated complement activation pathways, etc., which were significantly enriched in the DEGs. PPI analysis showed that IL-10, VEGFA, CXCL8, MMP9, and several histone-related genes were the hub genes with the highest degree scores. Moreover, IPA analysis showed that several proinflammatory pathways were upregulated, whereas antiinflammatory pathways were downregulated. The combination of NFSF14+TANK+ANKRD 33 B +HSPA1B was able to discriminate between AR and non-AR with an AUC of 92.3% (95% CI 82.8–100). Characterisation of PBMCs by RNA-Seq and bioinformatics analysis demonstrated gene signatures and biological pathways associated with AR. Our study may provide the foundation for the discovery of biomarkers and an in-depth understanding of acute renal allograft rejection.

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IL-1 induces mitochondrial translocation of IRAK2 to suppress oxidative metabolism in adipocytes

Cited by 36 publications

References 58 publications

Mitochondria May Mediate Prenatal Environmental Influences in Autism Spectrum Disorder

Mitochondria May Mediate Prenatal Environmental Influences in Autism Spectrum Disorder

Mitofusin 2 Deficiency Causes Pro-Inflammatory Effects in Human Primary Macrophages

Pre-transplant Transcriptional Signature in Peripheral Blood Mononuclear Cells of Acute Renal Allograft Rejection

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