Eicosanoid storm in infection and inflammation

Dennis, Edward A.; Norris, Paul C.

doi:10.1038/nri3859

Cited by 1,192 publications

(1,174 citation statements)

References 119 publications

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“…Prostaglandins, leukotrienes and lipoxins are groups of eicosanoids involved in pro-, and/or anti-inflammatory responses. During vasodilation prostaglandins and leukotrienes induce increased permeability of post capillary venules and also recruit complement components and leukocytes to the site of inflammation [2]. In contrast, lipoxins act as pro-resolving lipid mediators, as for example, LXA 4 inhibits the recruitment of neutrophil and eosinophil granulocytes in post capillary venules [3].…”

Section: Discussionmentioning

confidence: 99%

Eicosanoid biosynthesis influences the virulence of Candida parapsilosis

et al. 2018

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Lipid mediators, derived from arachidonic acid metabolism, play an important role in immune regulation. The functions of bioactive eicosanoids range from modulating cytokine signaling and inflammasome formation to anti-inflammatory and pro-resolving activities. Human pathogenic fungi such as Candida albicans, Candida parapsilosis, Cryptococcus neoformans and Aspergillus fumigatus have been shown to produce such lipid mediators, associated with their virulence. To date, investigations into the molecular mechanisms of fungal eicosanoid biosynthesis in different species have revealed that several genes are associated with prostaglandin production. However, these routes remain uncharacterized in C. parapsilosis with early results suggesting it uses pathways distinct from those found in C. albicans. Therefore, we aimed to identify and characterize C. parapsilosis genes involved in eicosanoid biosynthesis. Following arachidonic acid treatment of C. parapsilosis cells, we identified several genes interfering with prostaglandin production. Out of the identified genes, homologues of a multi copper oxidase (FET3), an Acyl-CoA thiolase (POT1) and an Acyl-CoA oxidase (POX1-3) were found to play a significant role in prostaglandin synthesis. Furthermore, all three genes were confirmed to enhance C. parapsilosis pathogenicity, as the corresponding deletion mutants were cleared more efficiently by human macrophages and induced higher levels of pro-inflammatory cytokines. In addition, the mutants were less virulent than the wild-type strain in a mouse model of systemic infection. Taken together, we identified three genes that regulate eicosanoid biosynthesis in C. parapsilosis and impact the fungus’ virulence.

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Section: Discussionmentioning

confidence: 99%

Eicosanoid biosynthesis influences the virulence of Candida parapsilosis

et al. 2018

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“…Interestingly, RvD1 was found to limit nuclear localization of 5-LO in Mfs via inhibition of calmodulindependent protein kinase II (48). As reviewed by Dennis and Norris (6), the availability of endogenous AA to the different COX and LOX enzymes and assembly of enzyme systems may also apply. Expression of 15-LOX-1 was higher in M-CSF Mfs as compared with GM-CSF cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Recently it was reported that LXA 4 and 15-epi-LXA 4 could also be formed within one cell type (murine RAW264.7 and bone marrow-derived Mfs) (8). Depending on the expression and activation of eicosanoid-forming enzymes and their proximity to cPLA 2 , cells may preferentially shunt AA toward one of these pathways (6). Lipidomic analysis has been applied to study AA metabolism in mouse peritoneal Mfs (9), RAW264.7 Mfs (10,11), mouse mast cells (12), and Mfs from mouse lung tumors (13).…”

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confidence: 99%

GM‐CSF– and M‐CSF–primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures

et al. 2017

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M1 and M2 activated macrophages (Mfs) have different roles in inflammation. Because pathogens may first encounter resting cells, we investigated lipid mediator profiles prior to full activation. Human monocytes were differentiated with granulocyte Mf colony-stimulating factor (GM-CSF) or Mf colony-stimulating factor (M-CSF), which are known to prime toward M1 or M2 phenotypes, respectively. Lipid mediators released during resting conditions and produced in response to bacterial stimuli (LPS/N-formylmethionyl-leucyl-phenylalanine or peptidoglycan) were quantified by liquid chromatography-mass spectrometry. In resting conditions, both Mf phenotypes released primarily proresolving lipid mediators (prostaglandin E 2 metabolite, lipoxin A 4 , and 18-hydroxyeicosapentaenoic acid). A striking shift toward proinflammatory eicosanoids was observed when the same cells were exposed (30 min) to bacterial stimuli: M-CSF Mfs produced considerably more 5-lipoxygenase products, particularly leukotriene C 4 , potentially linked to M2 functions in asthma. Prostaglandins were formed by both Mf types. In the M-CSF cells, there was also an enhanced release of arachidonic acid and activation of cytosolic phospholipase A 2 . However, GM-CSF cells expressed higher levels of 5-lipoxygenase and 5-lipoxygenase-activating protein, and in ionophore incubations these cells also produced the highest levels of 5-hydroxyeicosatetraenoic acid. In summary, GM-CSF and M-CSF Mfs displayed similar proresolving lipid mediator formation in resting conditions but shifted toward different proinflammatory eicosanoids upon bacterial stimuli. This demonstrates that preference for specific eicosanoid pathways is primed by CSFs before full M1/M2 activation.-Lukic, A., Larssen, P., Fauland, A., Samuelsson, B., Wheelock, C. E., Gabrielsson, S., Radmark, O. GM-CSF-and M-CSF-primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures. FASEB J. 31, 4370-4381 (2017). www.fasebj.orgMacrophages (Mfs) orchestrate the inflammatory process from early onset to the resolution phase (1, 2). A major issue in Mf biology is to characterize functional phenotypes, currently described as a heterogeneous spectrum of activated states, from M1 to M2 (3, 4). Stimulating factors, such as cytokines and pathogens, can induce specific phenotypes: originally IFN-g + LPS activation resulted in a proinflammatory M1 state, whereas IL-4 activation induced the alternatively activated M2 state. Polarized cells express distinct markers, such as transcription factors, cytokines, and surface markers; these are the main tools to define Mf phenotypes. A number of transcripts have been reported to differ between M1 and M2 Mfs, including mRNAs for enzymes involved in eicosanoid metabolism (5).Eicosanoids originate from arachidonic acid (AA), released from membrane phospholipids by phospholipases, typically cytosolic phospholipase A 2 (cPLA 2 ) (6). Free AA is further metabolized via 3 enzymatic pathways: lipoxygenase (LO), cyclooxygenase (COX), and cyto...

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“…Of course, we were excited to see that the new questions raised by their discoveries pointed back to our favorite enzyme, PLA 2 . Specifically, free arachidonic acid is at very low levels in cells and is generated spontaneously as needed for prostaglandin/leukotriene biosynthesis; PLA 2 is responsible for the initiation of this arachidonic acid cascade (9,78,81) (Fig. 6).…”

Section: A Turning Point For Lipid Signalingmentioning

confidence: 99%

“…Back in my laboratory, lipid cell signaling had always been focused on the metabolites of arachidonic acid-the eicosanoids and related oxidized polyunsaturated fatty acids (PUFA)-that activate a large variety of G-coupled protein receptors (GPCRs) (81). We had already learned through our work on cobra venom sPLA 2 that inhibitors could help us interrogate enzymes, but the inhibitors that worked on sPLA 2 didn't necessarily translate well to the mammalian systems, especially the intracellular PLA 2 s that now occupied our attention.…”

Section: A Turning Point For Lipid Signalingmentioning

confidence: 99%

Liberating Chiral Lipid Mediators, Inflammatory Enzymes, and LIPID MAPS from Biological Grease

Dennis

2016

Journal of Biological Chemistry

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In 1970, it was well accepted that the central role of lipids was in energy storage and metabolism, and it was assumed that amphipathic lipids simply served a passive structural role as the backbone of biological membranes. As a result, the scientific community was focused on nucleic acids, proteins, and carbohydrates as information-containing molecules. It took considerable effort until scientists accepted that lipids also "encode" specific and unique biological information and play a central role in cell signaling. Along with this realization came the recognition that the enzymes that act on lipid substrates residing in or on membranes and micelles must also have important signaling roles, spurring curiosity into their potentially unique modes of action differing from those acting on water-soluble substrates. This led to the creation of the concept of "surface dilution kinetics" for describing the mechanism of enzymes acting on lipid substrates, as well as the demonstration that lipid enzymes such as phospholipase A 2 (PLA 2 ) contain allosteric activator sites for specific phospholipids as well as for membranes. As our understanding of phospholipases advanced, so did the understanding that many of the lipids released by these enzymes are chiral informationcontaining signaling molecules; for example, PLA 2 regulates the generation of precursors for the biosynthesis of eicosanoids and other bioactive lipid mediators of inflammation and resolution underlying disease progression. The creation of the LIPID MAPS initiative in 2003 and the ensuing development of the lipidomics field have revealed that lipid metabolites are central to human metabolism. Today lipids are recognized as key mediators of health and disease as we enter a new era of biomarkers and personalized medicine. This article is my personal "reflection" on these scientific advances.

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Eicosanoid storm in infection and inflammation

Cited by 1,192 publications

References 119 publications

Eicosanoid biosynthesis influences the virulence of Candida parapsilosis

Eicosanoid biosynthesis influences the virulence of Candida parapsilosis

GM‐CSF– and M‐CSF–primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures

Liberating Chiral Lipid Mediators, Inflammatory Enzymes, and LIPID MAPS from Biological Grease

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