Inhibition of 5-lipoxygenase alleviates graft-versus-host disease

Rezende, Bárbara Antunes; Athayde, Rayssa Maciel; Gonçalves, William; Resende, Carolina Braga de; Bernardes, Priscila Teles de Toledo; Perez, Denise; Esper, Lísia; Reis, Alesandra C.; Rachid, Milene Alvarenga; Castor, Marina Gomes Miranda e; Cunha, Thiago Mattar; Machado, Fabiana S.; Teixeira, Mauro Martins; Pinho, Vanessa

doi:10.1084/jem.20170261

Cited by 18 publications

(19 citation statements)

References 77 publications

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“…Leukotrienes are secreted into the extracellular space and play a crucial role in the inflammatory response to injury [36]. After cellular stimulation, 5-LO is translocated to the nuclear membrane and activated by 5-LO-activating protein (FLAP), a nuclear membrane protein [37]. During this process, 5-LO catalyzes the oxygenation of AA, followed by a dehydration step to produce the epoxide intermediate LTA 4 .…”

Section: Discussionmentioning

confidence: 99%

Anti-Allergic and Anti-Inflammatory Effects of Kuwanon G and Morusin on MC/9 Mast Cells and HaCaT Keratinocytes

Jin

Shin

et al. 2019

Molecules

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Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disease. The use of immunomodulatory corticosteroids in AD treatment causes adverse side effects. Therefore, novel natural anti-inflammatory therapeutics are needed. The aim of the present study was to investigate the anti-allergic and anti-inflammatory activities of kuwanon G and morusin. To investigate the effect of kuwanon G and morusin on skin inflammation, enzyme-linked immunosorbent assays (ELISA) to quantitate secreted (RANTES/CCL5), thymus- and activation-regulated chemokine (TARC/CCL17), and macrophage-derived chemokine (MDC/CCL22) were performed, followed by Western blotting to measure the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and nuclear transcription factor-κB (NF-κB) p65 in tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)-stimulated HaCaT keratinocytes. In order to evaluate the anti-allergic effects, ELISA to quantify histamine and leukotriene C4 (LTC4) production and Western blotting to measure 5-lipoxygenase (5-LO) activation were performed using PMA and A23187-stimulated MC/9 mast cells. Kuwanon G reduced the release of RANTES/CCL5, TARC/CCL17, and MDC/CCL22 via down-regulation of STAT1 and NF-κB p65 signaling in TNF-α and IFN-γ-stimulated HaCaT keratinocytes. Kuwanon G also inhibited histamine production and 5-LO activation in PMA and A23187-stimulated MC/9 mast cells. Morusin inhibited RANTES/CCL5 and TARC/CCL17 secretion via the suppression of STAT1 and NF-κB p65 phosphorylation in TNF-α and IFN-γ-stimulated HaCaT keratinocytes, and the release of histamine and LTC4 by suppressing 5-LO activation in PMA and A23187-stimulated MC/9 mast cells. Kuwanon G and morusin are potential anti-inflammatory mediators for the treatment of allergic and inflammatory skin diseases such as AD.

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Section: Discussionmentioning

confidence: 99%

Anti-Allergic and Anti-Inflammatory Effects of Kuwanon G and Morusin on MC/9 Mast Cells and HaCaT Keratinocytes

Jin

Shin

et al. 2019

Molecules

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“…For generation of bone marrow chimeras, four to eightweek-old female mice were irradiated 9 Gy total-body radiation (source 60 Co) in two doses at 2 h intervals to minimize gastrointestinal toxicity and then given an i.v. infusion of 1 × 10 7 BM cells from C57BL/6 or SOCS2 -/mice as previously described [19]. Split irradiation reduced the number of animals succumbing to irradiation to under 3%.…”

Section: Methodsmentioning

confidence: 99%

Role of SOCS2 in the Regulation of Immune Response and Development of the Experimental Autoimmune Encephalomyelitis

Cramer

Oliveira

Leite

et al. 2019

Mediators of Inflammation

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Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). Experimental Autoimmune Encephalomyelitis (EAE) is the most widely used animal model for the study of MS. The Suppressor of Cytokine Signaling (SOCS) 2 protein plays a critical role in regulating the immune responses. The role of SOCS2 during EAE has not been explored. EAE was induced in WT and SOCS2-/- mice using myelin oligodendrocyte glycoprotein (MOG35-55) peptide. Brain and spinal cord were examined during the peak (day 14) and recovery phase (day 28) of the disease. SOCS2 was upregulated in the brain of WT mice at the peak and recovery phase of EAE. The development of the acute phase was slower in onset in SOCS2-/- mice and was associated with reduced number of Th1 (CD3+CD4+IFN-γ+) cells in the spinal cord and brain. However, while in WT mice, maximal clinical EAE score was followed by a progressive recovery; the SOCS2-/- mice were unable to recover from locomotor impairment that occurred during the acute phase. There was a prolonged inflammatory response (increased Th1 and decreased Th2 and T regulatory cells) in the late phase of EAE in the CNS of SOCS2-/- mice. Transplantation of bone marrow cells from SOCS2-/- into irradiated WT mice resulted in higher lethality at the early phase of EAE. Altogether, these results suggest that SOCS2 plays a dual role in the immune response during EAE. It is necessary for damage during the acute phase damage but plays a beneficial role in the recovery stage of the disease.

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“…Leukotriene or prostaglandin are known to be associated with generation of pro-inflammatory cytokines like interferon-γ, TNF-α, and IL-17, and gut integrity respectively. Inhibition of 5-lipoxygenase (5-LO) which reduces leukotriene B4 generation from arachidonic acid has been shown to protect mice from aGVHD (Rezende et al, 2017).…”

Section: Lipids and Their Derivativesmentioning

confidence: 99%

“…(Kominsky et al, 2010) 22 5-Lipoxygenase (5-LO) Inhibition Leukotriene or prostaglandin are known to be associated with generation of pro-inflammatory cytokines like interferon-γ, TNF-α, and IL-17, and gut integrity respectively. Inhibition of 5-lipoxygenase (5-LO) which reduces leukotriene B4 generation from arachidonic acid has been shown to protect mice from aGVHD (Rezende et al, 2017). (Rezende et al, 2017) 23 L-carnitine acyltransferases Inhibition L-Carnitine acyltransferases catalyze the reversible transfer of acyl groups between coenzyme A and L-carnitine, converting acyl-CoA esters into acyl-carnitine esters.…”

Section: Inhibitionmentioning

confidence: 99%

“…Inhibition of 5-lipoxygenase (5-LO) which reduces leukotriene B4 generation from arachidonic acid has been shown to protect mice from aGVHD (Rezende et al, 2017). (Rezende et al, 2017) 23 L-carnitine acyltransferases Inhibition L-Carnitine acyltransferases catalyze the reversible transfer of acyl groups between coenzyme A and L-carnitine, converting acyl-CoA esters into acyl-carnitine esters. Isobutyrylcarnitine and propyonylcarnitine levels which are crucial for the transport of fatty acids and the release of immunoregulatory cytokines, were higher in pretransplant samples of patients who later developed GVHD.…”

Section: Inhibitionmentioning

confidence: 99%

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Metabolic Reprogramming—A New Era How to Prevent and Treat Graft Versus Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation Has Begun

Kumari

Palaniyandi

2020

Front. Pharmacol.

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Allogeneic hematopoietic stem cell transplantation (HSCT) is the solitary therapeutic therapy for many types of hematological cancers. The benefits of this procedure are challenged by graft vs. host disease (GVHD), causing significant morbidity and mortality. Recent advances in the metabolomics field have revolutionized our understanding of complex human diseases, clinical diagnostics and allow to trace the de novo biosynthesis of metabolites. There is growing evidence for metabolomics playing a role in different aspects of GVHD, and therefore metabolomic reprogramming presents a novel tool for this disease. Pre-transplant cytokine profiles and metabolic status of allogeneic transplant recipients is shown to be linked with a threat of acute GVHD. Immune reactions underlying the pathophysiology of GVHD involve higher proliferation and migration of immune cells to the target site, requiring shifts in energy supply and demand. Metabolic changes and reduced availability of oxygen result in tissue and cellular hypoxia which is extensive enough to trigger transcriptional and translational changes. T cells, major players in acute GVHD pathophysiology, show increased glucose uptake and glycolytic activity. Effector T (Teff) cells activated during nutrient limiting conditions in vitro or multiplying during GVHD in vivo, depend more on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Dyslipidemia, such as the increase of medium and long chain fatty and polyunsaturated acids in plasma of GVHD patients, has been observed. Sphingolipids associate with inflammatory conditions and cancer. Chronic GVHD (cGVHD) patients show reduced branched-chain amino acids (BCAAs) and increased sulfur-containing metabolites post HSCT. Microbiota-derived metabolites such as aryl hydrocarbon receptor (AhR) ligands, bile acids, plasmalogens and short chain fatty acids vary significantly and affect allogeneic immune responses during acute GVHD. Considering the multitude of possibilities, how altered metabolomics are involved in GVHD biology, multi-timepoints related and multivariable biomarker panels for prognosticating and understanding GVHD are needed. In this review, we will discuss the recent work addressing metabolomics reprogramming to control GVHD in detail.

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Inhibition of 5-lipoxygenase alleviates graft-versus-host disease

Cited by 18 publications

References 77 publications

Anti-Allergic and Anti-Inflammatory Effects of Kuwanon G and Morusin on MC/9 Mast Cells and HaCaT Keratinocytes

Anti-Allergic and Anti-Inflammatory Effects of Kuwanon G and Morusin on MC/9 Mast Cells and HaCaT Keratinocytes

Role of SOCS2 in the Regulation of Immune Response and Development of the Experimental Autoimmune Encephalomyelitis

Metabolic Reprogramming—A New Era How to Prevent and Treat Graft Versus Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation Has Begun

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