12/15-lipoxygenase–mediated enzymatic lipid oxidation regulates DC maturation and function

Rothe, Tobias; Грубер, Флориан; Uderhardt, Stefan; Ipseiz, Natacha; Rößner, Susanne; Oskolkova, Olga; Blüml, Stephan; Leitinger, Norbert; Bicker, Wolfgang; Bochkov, Valery N.; Yamamoto, Masayuki; Steinkasserer, Alexander; Schett, Georg; Zinser, Elisabeth; Krönke, Gerhard

doi:10.1172/jci78490

Cited by 85 publications

(83 citation statements)

References 45 publications

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“…In this genetic background, either DHA supplementation or in vivo injection of RvD1 in anti-CD3 treated mice reduced the activation of T H 1 and T H 17 cells and restored Treg cell numbers. In line with this, it has also been shown that deletion or pharmacological inhibition of SPM-generating 12/15-lipoxygenase regulated murine and human dendritic cell maturation and activation, favoring T H 17 differentiation of CD4+ T cells (38), thus highlighting the critical role for SPMs in modulating T helper responses. The recent identification of SPMs in human secondary lymphoid organs (11), where most naïve-to-effector or iTreg differentiation happens, provides in vivo relevance of our findings.…”

Section: Discussionmentioning

confidence: 71%

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: 71%

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

et al. 2016

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“…These oxidized fatty acids have been implicated as important mediators of immune responses, including involvement in macrophage differentiation [24] and dendritic cell maturation [25]. They have also been directly implicated in the pathogenesis of atherosclerosis [8, 9].…”

Section: Discussionmentioning

confidence: 99%

High levels of oxidized fatty acids in HDL are associated with impaired HDL function in patients with active rheumatoid arthritis

et al. 2017

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The objective of this study was to evaluate oxidation products of arachidonic acid and linoleic acid in lipoproteins and synovial fluid (SF) from patients with active rheumatoid arthritis (RA) compared to non-RA controls. High-density lipoproteins (HDL) and low-density lipoproteins (LDL) were isolated from plasma using fast protein liquid chromatography and HDL was isolated from SF using dextran sulfate precipitation. 5-Hydroxyeicosatetraenoic acid (HETE), 12-HETE, 15-HETE, 9 hydroxyoctadecadienoic (HODE), and 13-HODE levels were measured in HDL, LDL, and SF by liquid chromatography–tandem mass spectrometry. HDL’s anti-inflammatory function, cholesterol levels, myeloperoxidase (MPO) and paraoxonase 1 (PON1) activities were determined as previously. 5-HETE, 15-HETE, 9-HODE, and 13-HODE levels were significantly increased in HDL and LDL from patients with active RA (n = 10) compared to healthy controls (n = 8) and correlated significantly with measures of systemic inflammation, particularly in HDL (r = 0.65–0.80, p values < 0.004). Higher HETES and HODES in HDL were also significantly correlated with impaired HDL function as measured by the HDL inflammatory index (HII) (r = 0.54–0.58; p values < 0.03). 15-HETE levels and MPO activity were higher in RA SF (n = 10) compared to osteoarthritis (OA) SF(n = 11), and HDL from RA SF had worse function compared to OA SF HDL (HII = 2.1 ± 1.9 and 0.5 ± 0.1), respectively (p < 0.05). Oxidation products of arachidonic acid and linoleic acid are increased in HDL and LDL from patients with active RA compared to healthy controls, and are associated with worse anti- oxidant function of HDL. These results suggest a potential mechanism by which oxidative stress from active RA increases oxidized fatty acids in HDL, promoting HDL dysfunction, and thereby increasing atherosclerotic risk.

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“…The presence of oxidized PC (OxPC) on the surface of apoptotic cells has been demonstrated using the monoclonal antibody EO6, which exclusively binds to OxPC[16–19]. Furthermore, enzymatic oxidation of phospholipids involving 12/15 lipoxygenase produces biologically active mediators[20, 21]. The cholesteryl esters found within LDL are also subject to oxidative modification, which may contribute to endothelial activation[22].…”

Section: Structures and Biological Functions Of Oxidized Phospholipidsmentioning

confidence: 99%

“…In this context, OxPL were shown to be important recognition signals on apoptotic cells[18], which could facilitate phagocytosis by macrophages[15, 67]. The Tabas group showed that OxPL induce apoptosis in macrophages undergoing ER-stress via CD36/TLR2 activation[68] and Gerhard Kronke’s group reported that 12/15 lipoxygenase plays a major and unexpected role in the non-inflammatory clearance of apoptotic cells, via a mechanism involving the formation of oxidized phosphatidylethanolamines (OxPE)[20]. On the other hand, phagocytosis was shown to be inhibited in macrophages by mm-LDL[69] and OxPAPC[58], and Sylvia Knapp’s group discovered that this inhibition involves WAVE1[70, 71], which is a cytoskeleton bound A-kinase anchoring protein.…”

Section: Oxpl and Macrophages: Identification Of Moxmentioning

confidence: 99%

The effect of oxidized phospholipids on phenotypic polarization and function of macrophages

Serbulea

DeWeese

Leitinger

2017

Free Radical Biology and Medicine

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Oxidized phospholipids are products of lipid oxidation that are found on oxidized low-density lipoproteins and apoptotic cell membranes. These biologically active lipids were shown to affect a variety of cell types and attributed pro-as well as anti-inflammatory effects. In particular, macrophages exposed to oxidized phospholipids drastically change their gene expression pattern and function. These ‘Mox,’macrophages were identified in atherosclerotic lesions, however, it remains unclear how lipid oxidation products are sensed by macrophages and how they influence their biological function. Here, we review recent developments in the field that provide insight into the structure, recognition, and downstream signaling of oxidized phospholipids in macrophages.

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12/15-lipoxygenase–mediated enzymatic lipid oxidation regulates DC maturation and function

Cited by 85 publications

References 45 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

High levels of oxidized fatty acids in HDL are associated with impaired HDL function in patients with active rheumatoid arthritis

The effect of oxidized phospholipids on phenotypic polarization and function of macrophages

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