Untargeted Plasma Metabolomics Identifies Endogenous Metabolite with Drug-like Properties in Chronic Animal Model of Multiple Sclerosis

Poisson, Laila; Salehiniya, Hamid; Singh, Jaspreet; Datta, Indrani; Denic, Aleksandar; Łabuzek, Krzysztof; Hoda, Nasrul; Shankar, Ashray; Kumar, Ashok; Cerghet, Mirela; Elias, Stanton B.; Mohney, Robert P.; Rodriguez, Moses; Rattan, Ramandeep; Mangalam, Ashutosh K.; Giri, Shailendra

doi:10.1074/jbc.m115.679068

Cited by 77 publications

(85 citation statements)

References 84 publications

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“…Although the role of each of the SPMs is highly associated with the resolution of acute inflammation operated by cells of innate immunity, it is becoming increasingly clear that these bioactive lipids might take part also in the control of chronic inflammation, possibly via acting on cells of adaptive immunity (20–23). In this regard, little systematic evidence for a direct role of these resolving mediators on the distinct adaptive cell populations has been assessed (24, 25).…”

Section: Discussionmentioning

confidence: 99%

Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses

et al. 2016

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Resolution of inflammation is a finely regulated process mediated by specialized pro-resolving lipid mediators (SPMs) including docosahexaenoic acid (DHA)-derived resolvins and maresins. The immunomodulatory role of SPMs in adaptive immune cells is of interest. Here, we report that the D-series resolvins Resolvin D1 and Resolvin D2 and Maresin 1 modulate adaptive immune responses in human peripheral blood lymphocytes. These lipid mediators reduce cytokine production by activated CD8 T cells and CD4 T-helper (TH) 1 and TH17 cells, but do not modulate T cell inhibitory receptors or abrogate their capacity to proliferate. Moreover, these SPMs prevented naïve CD4 T-cell differentiation into TH1 and TH17 by downregulating their signature transcription factors, T-bet and Rorc, in a mechanism mediated by the GPR32 and ALX/FPR2 receptors; they concomitantly enhanced de novo generation and function of Foxp3+ regulatory T (Treg) cells via the GPR32 receptor. These results were also supported in vivo in a mouse deficient for DHA synthesis (Elovl2−/−) that showed an increase in TH1/TH17 cells and a decrease in Treg cells compared to wild type mice. Additionally, either DHA supplementation in Elovl2−/− mice or in vivo administration of Resolvin D1 significantly reduced cytokine production upon specific stimulation of T cells. These findings demonstrate actions of specific SPMs on adaptive immunity and provide a new avenue for SPM-based approaches to modulate chronic inflammation.

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Section: Discussionmentioning

confidence: 99%

Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses

et al. 2016

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“…Cells isolated from the lymph nodes (LNs) of myelin MOG 35-55-immunized (2 3 10 6 /ml) Wt and a1KO mice were cultured in the presence of MOG (20 mg/ml). Cell proliferation and the production of various cytokines (IFN-g, IL-17A, IL-4, IL-6, IL-10, IL-1b, IL-23p19, and TGF-b) were examined as described before (13,18).…”

Section: Eae Induction and Recall Responsementioning

confidence: 99%

“…Quantitative PCR (qPCR) was performed using SYBR Green PCR master mix (Bio-Rad) and a Bio-Rad iCycler iQ PCR (Bio-Rad) using the following primers. Mouse primers for IFN-g, IL-17a, IL-4, T-bet, RORg, Gata3, IL-10, and AMPKa1 were published previously (13,18). Other primers were purchased from realtimeprimers.com (Elkins Park, PA).…”

Section: Brain Histology and Spinal Cord Pathologymentioning

confidence: 99%

AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type Macrophage–Th17 Axis

Mangalam

Rattan

Salehiniya

et al. 2016

The Journal of Immunology

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The AMP-activated protein kinase, AMPK, is an energy-sensing, metabolic switch implicated in various metabolic disorders; however, its role in inflammation is not well defined. We have previously shown that loss of AMPK exacerbates experimental autoimmune encephalomyelitis (EAE) disease severity. In this study, we investigated the mechanism through which AMPK modulates inflammatory disease like EAE. AMPKα1 knockout (α1KO) mice with EAE showed severe demyelination and inflammation in the brain and spinal cord compared with wild-type due to higher expression of proinflammatory Th17 cytokines, including IL-17, IL-23, and IL-1β, impaired blood–brain barrier integrity, and increased infiltration of inflammatory cells in the CNS. Infiltrated CD4 cells in the brains and spinal cords of α1KO with EAE were significantly higher compared with wild-type EAE and were characterized as IL-17 (IL-17 and GM-CSF double-positive) CD4 cells. Increased inflammatory response in α1KO mice was due to polarization of macrophages (Mϕ) to proinflammatory M1 type phenotype (IL-10lowIL-23/IL-1β/IL-6high), and these M1 Mϕ showed stronger capacity to induce allogenic as well as Ag-specific (myelin oligodendrocyte glycoprotein [MOG]35–55) T cell response. Mϕ from α1KO mice also enhanced the encephalitogenic property of MOG35–55–primed CD4 T cells in B6 mice. The increased encephalitogenic MOG-restricted CD4+ T cells were due to an autocrine effect of IL-1β/IL-23–mediated induction of IL-6 production in α1KO Mϕ, which in turn induce IL-17 and GM-CSF production in CD4 cells. Collectively, our data indicate that AMPK controls the inflammatory disease by regulating the M1 phenotype–Th17 axis in an animal model of multiple sclerosis.

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“…Similar to transcriptome analysis, the metabolic profiling, commonly referred to as metabolomics, has also attracted significant interest in various diseases, as it holds great promise in formulating a systems-level interpretation of biological events at the cellular or tissue levels (Isobe and Arita, 2014;Suhre, 2014;Yin et al, 2015). Indeed, our recent metabolomics studies led to the identification of resolvin D1 as an endogenous metabolite possessing drug-like properties, whose therapeutic efficacy was tested in preclinical mouse models of multiple sclerosis (Poisson et al, 2015). Similarly, we performed the global metabolomics on S. aureus (SA)infected mouse retina and discovered that the pathways involved in energy metabolism were significantly altered, as evidenced by a decrease in the enzymes of the TCA cycle and oxidative phosphorylation (unpublished data).…”

Section: Introductionmentioning

confidence: 99%

5-Aminoimidazole-4-carboxamide ribonucleoside-mediated adenosine monophosphate-activated protein kinase activation induces protective innate responses in bacterial endophthalmitis

Kumar

Giri

2016

Cellular Microbiology

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The retina is considered to be the most metabolically active tissue in the body. However, the link between energy metabolism and retinal inflammation, as incited by microbial infection such as endophthalmitis remains unexplored. In this study, using a mouse model of Staphylococcus aureus (SA) endophthalmitis, we demonstrate that the activity (phosphorylation) of AMP-activated protein kinase alpha (AMPKα), a cellular energy sensor, and its endogenous substrate; acetyl-CoA carboxylase (ACC) is downregulated in the SA-infected retina. Intravitreal administration of an AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) restored AMPKα and ACC phosphorylation. AICAR treatment reduced both the bacterial burden and intraocular inflammation in SA-infected eyes by inhibiting NF-κB and MAP kinases (p38 and JNK) signaling. The anti-inflammatory effects of AICAR were diminished in eyes pretreated with AMPK inhibitor, Compound C. The bioenergetics (Seahorse) analysis of SA-infected microglia and bone marrow-derived macrophages (BMDM) revealed an increase in glycolysis, which was reinstated by AICAR treatment. AICAR also reduced the expression of SA-induced glycolytic genes, including hexokinase 2 (HK2), and glucose transporter 1 (Glut1) in microglia, BMDM, and the mouse retina. Interestingly, AICAR treatment enhanced the bacterial phagocytic and intracellular killing activities of cultured microglia, macrophages, and neutrophils. Furthermore, AMPKα1 global knockout mice exhibited increased susceptibility towards SA endophthalmitis, as evidenced by increased inflammatory mediators and bacterial burden and reduced retinal function. Together, these findings provide the first evidence that AMPK activation promotes retinal innate defense in endophthalmitis by modulating energy metabolism, and that it can be targeted therapeutically to treat ocular infections.

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Untargeted Plasma Metabolomics Identifies Endogenous Metabolite with Drug-like Properties in Chronic Animal Model of Multiple Sclerosis

Cited by 77 publications

References 84 publications

Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses

Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses

AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type Macrophage–Th17 Axis

5-Aminoimidazole-4-carboxamide ribonucleoside-mediated adenosine monophosphate-activated protein kinase activation induces protective innate responses in bacterial endophthalmitis

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