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TNFR2/14-3-3ε signaling complex instructs macrophage plasticity in inflammation and autoimmunity

ABSTRACT: To elucidate the molecular mechanisms by which 14-3-3ε and PGRN regulates macrophage plasticity, we performed unbiased RNA-seq on BMDMs isolated from WT, PGRN-/- and 14-3-3ε-/- mice stimulated with pro-inflammatory LPS/IFNγ or anti-inflammatory IL-4.

ORGANISM(S): Mus musculus

PROVIDER: GSE172119 | GEO | 2022/04/14

REPOSITORIES: GEO

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TNFR2/14-3-3ε signaling complex instructs macrophage plasticity in inflammation and autoimmunity.

Project description:TNFR1 and TNFR2 have received prominent attention because of their dominance in the pathogenesis of inflammation and autoimmunity. TNFR1 has been extensively studied and primarily mediates inflammation. TNFR2 remains far less studied, although emerging evidence demonstrates that TNFR2 plays an antiinflammatory and immunoregulatory role in various conditions and diseases. Herein, we report that TNFR2 regulates macrophage polarization, a highly dynamic process controlled by largely unidentified intracellular regulators. Using biochemical copurification and mass spectrometry approaches, we isolated the signaling molecule 14-3-3ε as a component of TNFR2 complexes in response to progranulin stimulation in macrophages. In addition, 14-3-3ε was essential for TNFR2 signaling-mediated regulation of macrophage polarization and switch. Both global and myeloid-specific deletion of 14-3-3ε resulted in exacerbated inflammatory arthritis and counteracted the protective effects of progranulin-mediated TNFR2 activation against inflammation and autoimmunity. TNFR2/14-3-3ε signaled through PI3K/Akt/mTOR to restrict NF-κB activation while simultaneously stimulating C/EBPβ activation, thereby instructing macrophage plasticity. Collectively, this study identifies 14-3-3ε as a previously unrecognized vital component of the TNFR2 receptor complex and provides new insights into the TNFR2 signaling, particularly its role in macrophage polarization with therapeutic implications for various inflammatory and autoimmune diseases with activation of the TNFR2/14-3-3ε antiinflammatory pathway.

| S-EPMC8363273 | biostudies-literature

TNFR2/14-3-3ε signaling complex instructs macrophage plasticity in inflammation and autoimmunity

Project description:TNFR2/14-3-3ε signaling complex instructs macrophage plasticity in inflammation and autoimmunity

| PRJNA722159 | ENA

14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis [single-cell RNA-seq]

Project description:To unravel the relative abundance and distribution of PGRN, TNFR2, and 14-3-3ε mRNA transcripts in different chondrocyte subpopulations, we performed single-cell RNA-seq (scRNA-seq) in chondrocytes isolated from human OA and normal cartilage.

2022-03-10 | GSE169454 | GEO

Megasphaera elsdenii 14-14

Project description:Megasphaera elsdenii 14-14 Genome Sequence

| PRJNA237235 | ENA

Intrinsic TNFR2 signaling in T regulatory cells provides protection in CNS autoimmunity.

Project description:TNF is a multifunctional cytokine involved in autoimmune disease pathogenesis that exerts its effects through two distinct TNF receptors, TNFR1 and TNFR2. While TNF- and TNFR1-deficient (but not TNFR2-deficient) mice show very similar phenotypes, the significance of TNFR2 signaling in health and disease remains incompletely understood. Recent studies implicated the importance of the TNF/TNFR2 axis in T regulatory (Treg) cell functions. To definitively ascertain the significance of TNFR2 signaling, we generated and validated doubly humanized TNF/TNFR2 mice, with the option of conditional inactivation of TNFR2. These mice carry a functional human TNF-TNFR2 (hTNF-hTNFR2) signaling module and provide a useful tool for comparative evaluation of TNF-directed biologics. Conditional inactivation of TNFR2 in FoxP3+ cells in doubly humanized TNF/TNFR2 mice down-regulated the expression of Treg signature molecules (such as FoxP3, CD25, CTLA-4, and GITR) and diminished Treg suppressive function in vitro. Consequently, Treg-restricted TNFR2 deficiency led to significant exacerbation of experimental autoimmune encephalomyelitis (EAE), accompanied by reduced capacity to control Th17-mediated immune responses. Our findings expose the intrinsic and beneficial effects of TNFR2 signaling in Treg cells that could translate into protective functions in vivo, including treatment of autoimmunity.

| S-EPMC6304938 | biostudies-literature

Nitric oxide modulates metabolic remodelling and immunometabolism in inflammatory murine macrophages

Project description:Classical stimulation of macrophages (MLPS/IFNγ) elicits the expression of inducible nitric oxide synthase (iNOS), generating large amounts of nitric oxide (NO) and inhibiting respiration. Consequent upregulation of glycolysis and a disrupted tricarboxylic acid (TCA) cycle underpin this switch to a pro-inflammatory phenotype. Here we show that the NOS cofactor tetrahydrobiopterin (BH4) modulates key aspects of metabolic remodelling in activated bone-marrow-derived macrophages (BMDMs) via NO production. Using two complementary mouse models that each lack the capacity for inducible NO generation, through different mechanisms, we reveal that NO regulates macrophage respiratory function via changes in the abundance of critical N-module subunits in Complex I, by HIF1α-mediated glycolytic remodelling, and by modulating levels of the critical TCA cycle metabolites, and inflammatory mediators, citrate, succinate, and itaconate. Taken together, our findings reveal new critical roles for iNOS-derived NO that are required for metabolic remodelling and cytokine production in macrophage inflammatory responses.

2019-05-31 | PXD010628 | Pride

Panicum virgatum cultivar:SAP-14-14

Project description:Panicum virgatum exome capture - SAP-14-14

| PRJNA447726 | ENA

Methylophilus sp. 14 strain:14

Project description:Methylophilus sp. 14 strain:14 Genome sequencing and assembly

| PRJNA670154 | ENA

Aeromonas hydrophila 14 strain:14

Project description:Aeromonas hydrophila 14 strain:14 Genome sequencing and assembly

| PRJNA183195 | ENA

CTRP6 promotes macrophage inflammatory response and its deficiency attenuates LPS-induced inflammation

Project description:Macrophages play critical roles in inflammation and tissue homeostasis, and their functions are regulated by various autocrine, paracrine, and endocrine factors. We have previously shown that CTRP6, a secreted protein of the C1q family, targets both adipocytes and macrophages to promote obesity-linked inflammation in adipose tissue. However, the gene programs and signaling pathways directly regulated by CTRP6 in macrophage remain unknown. Here, we combine transcriptomic and phosphoproteomic analyses to show that CTRP6 activates inflammatory gene programs and signaling pathways in bone marrow-derived macrophages (BMDMs). Treatment of BMDMs with CTRP6 upregulates proinflammatory, and suppresses the anti-inflammatory, gene expression. We show that CTRP6 activates p44/42-MAPK, p38-MAPK, and NF-κB signalings to promote inflammatory cytokine secretion from BMDMs, and that pharmacologic inhibition of these signaling pathways largely abolish the effects of CTRP6. Pretreatment of BMDMs with CTRP6 further augments LPS-induced inflammatory signaling and cytokine secretion from BMDMs. Consistent with the metabolic phenotype of proinflammatory M1-like macrophages, CTRP6 treatment induces a shift toward aerobic glycolysis and lactate production, reduces oxidative metabolism, and elevates mitochondrial ROS production in BMDMs. We use a Ctrp6 knockout mouse model to further confirm the physiologic relevance of our in vitro findings. BMDMs from CTRP6-deficient mice are less inflammatory at baseline and show a marked suppression of LPS-induced inflammatory gene expression and cytokine secretion. Loss of CTRP6 in mice also dampens LPS-induced inflammation and hypothermia. Collectively, we provide mechanistic evidence that CTRP6 regulates macrophage function, and neutralizing CTRP6 activity may have beneficial effects in reducing inflammation.

2024-01-26 | PXD042268 | Pride

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