Lipid mediator metabolic profiling demonstrates differences in eicosanoid patterns in two phenotypically distinct mast cell populations

Lundström, Susanna L.; Saluja, Rohit; Adner, Mikael; Haeggström, Jesper Z.; Nilsson, Gunnar; Wheelock, Craig E.

doi:10.1194/jlr.m030171

Cited by 35 publications

(35 citation statements)

References 53 publications

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“…This was found both in early work (20) and in recent lipidomic analyses (21)(22)(23)(24). Likewise, eosinophils (25)(26)(27) and mast cells (28)(29)(30)(31)(32) produce mainly LTC 4 , but apparently no or only small amounts of LTD 4 . Here we show transcellular conversion of leukocyte-derived LTC 4 to LTD 4 by A549 lung cancer cells expressing both GGT1 and GGT5, and by normal human primary bronchial epithelial cells (PBECs) expressing GGT5.…”

Section: Timeline Of Cell Culture and Coculturementioning

confidence: 68%

“…In all these studies, incubation times were at most 60 min. Likewise, eosinophils (25)(26)(27) and mast cells (28)(29)(30)(31)(32) produce mainly LTC 4 , but apparently no or only small amounts of LTD 4 . Interestingly, in mast cells cocultured with 3T3 fibroblasts [lacking GGT (48)], LTC 4 was also the major CysLT produced (29).…”

Section: Formation Of Cyslt In Coincubations Of Pbecs With Mm6 Cellsmentioning

confidence: 99%

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Pulmonary epithelial cancer cells and their exosomes metabolize myeloid cell-derived leukotriene C4 to leukotriene D4

Lukić

Jie

Idborg

et al. 2016

Journal of Lipid Research

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Leukotrienes (LTs) are mediators of inflammation (1) formed by immune cells in response to pathogens or danger signals. When cells are stimulated, cytosolic phospholipase A 2  (cPLA 2 ) and 5-lipoxygenase (LO) migrate to the nuclear membrane, arachidonic acid (AA) is released from nuclear membrane phospholipids, and LTA 4 is produced (2). Efficient translocation and activation of 5-LO requires two scaffold proteins, 5-LO activating protein (FLAP) and coactosin-like protein (CLP) (3). LTA 4 is then further metabolized by cytosolic LTA 4 hydrolase to LTB 4 , or by LTC 4 synthase (LTC 4 S) to LTC 4 . LTC 4 S is primarily located at the nuclear membrane together with FLAP, and both proteins are members of the family of membrane bound proteins involved in eicosanoid and glutathione metabolism (MAPEG). LTC 4 and its metabolites, LTD 4 and LTE 4 , are jointly referred to as the cysteinyl LTs (CysLTs). CysLTs elicit edema formation, mucus secretion, and smooth muscle contraction, as well as eosinophil trafficking and tissue remodeling, and thus contribute to symptoms in several chronic inflammatory diseases, such as asthma (4). There are at least three different receptors for the CysLTs; in the lung, bronchoconstriction and other effects are mediated via CysLT1. LTD 4 has a 10-to 50-fold higher potency for activation of CysLT1 compared with LTC 4 , while LTE 4 is the least active (5, 6). Thus, metabolism of LTC 4 to LTD 4 may have a considerable impact on CysLT1-mediated effects, also depending on further conversion to LTE 4 . Abstract Leukotrienes (LTs

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Section: Timeline Of Cell Culture and Coculturementioning

confidence: 68%

Section: Formation Of Cyslt In Coincubations Of Pbecs With Mm6 Cellsmentioning

confidence: 99%

Pulmonary epithelial cancer cells and their exosomes metabolize myeloid cell-derived leukotriene C4 to leukotriene D4

Lukić

Jie

Idborg

et al. 2016

Journal of Lipid Research

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“…To understand whether the developing MoDCs produce PPARg stimulatory compounds differentially in dense and sparse cultures, we performed a lipid metabolic profiling (16) in day-2 MoDCs and in their supernatants using the cell culture densities 2 3 10 6 , 0.5 3 10 6 , or 0.125 3 10 6 monocytes/ml. Fig.…”

Section: Similar Peroxisome Proliferator-activated Receptor G Activitmentioning

confidence: 99%

“…Lipid mediator analyses were performed as described previously (16). Analytical standards and isotopically labeled internal standards (Supplemental Table I) were purchased from Cayman Chemicals, Larodan Fine Chemicals (Malmo, Sweden) or Enzo Life Sciences (Farmingdale, NY).…”

Section: Lipid Measurementmentioning

confidence: 99%

Dendritic Cell Reprogramming by Endogenously Produced Lactic Acid

Nasi

Fekete

Krishnamurthy

et al. 2013

The Journal of Immunology

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147

118

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The demand for controlling T cell responses via dendritic cell (DC) vaccines initiated a quest for reliable and feasible DC modulatory strategies that would facilitate cytotoxicity against tumors or tolerance in autoimmunity. We studied endogenous mechanisms in developing monocyte-derived DCs (MoDCs) that can induce inflammatory or suppressor programs during differentiation, and we identified a powerful autocrine pathway that, in a cell concentration–dependent manner, strongly interferes with inflammatory DC differentiation. MoDCs developing at low cell culture density have superior ability to produce inflammatory cytokines, to induce Th1 polarization, and to migrate toward the lymphoid tissue chemokine CCL19. On the contrary, MoDCs originated from dense cultures produce IL-10 but no inflammatory cytokines upon activation. DCs from high-density cultures maintained more differentiation plasticity and can develop to osteoclasts. The cell concentration–dependent pathway was independent of peroxisome proliferator–activated receptor γ (PPARγ), a known endogenous regulator of MoDC differentiation. Instead, it acted through lactic acid, which accumulated in dense cultures and induced an early and long-lasting reprogramming of MoDC differentiation. Our results suggest that the lactic acid–mediated inhibitory pathway could be efficiently manipulated in developing MoDCs to influence the immunogenicity of DC vaccines.

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“…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). Lipid mediators released from fully activated M1 and M2 human Mfs have also been determined (14).…”

mentioning

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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Lipid mediator metabolic profiling demonstrates differences in eicosanoid patterns in two phenotypically distinct mast cell populations

Cited by 35 publications

References 53 publications

Pulmonary epithelial cancer cells and their exosomes metabolize myeloid cell-derived leukotriene C4 to leukotriene D4

Pulmonary epithelial cancer cells and their exosomes metabolize myeloid cell-derived leukotriene C4 to leukotriene D4

Dendritic Cell Reprogramming by Endogenously Produced Lactic Acid

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

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