Lipid droplets in activated mast cells – a significant source of triglyceride-derived arachidonic acid for eicosanoid production

LDs (lipid droplets) are metabolically highly active intracellular organelles. The lipid and protein profiles of LDs are cell-type-specific, and they undergo dynamic variation upon changes in the physiological state of a cell. It is well known that the main function of the LDs in adipocytes is to ensure energy supply and to maintain lipid homoeostasis in the body. In contrast, LDs in inflammatory cells have been implicated in eicosanoid biosynthesis, particularly under inflammatory conditions, thereby enabling them to regulate immune responses. Human mast cells are potent effector cells of the innate immune system, and the triacylglycerol (triglyceride) stores of their cytoplasmic LDs have been shown to contain large amounts of arachidonic acid, the main precursor of pro-inflammatory eicosanoids. In the present review, we discuss the current knowledge about the formation and function of LDs in inflammatory cells with specific emphasis on arachidonic acid and eicosanoid metabolism. On the basis of findings reported previously and our new observations, we propose a model in which lipolysis of LD-triacylglycerols provides arachidonic acid for lipid mediator generation in human mast cells.

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Activation of Mast Cells by NSAIDs Releases Arachidonic Acid Metabolites Independent of Histamine via a non-PPARγ Signaling Pathway

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2009.12.699 ◽

2010 ◽

Vol 125 (2) ◽

pp. AB179 ◽

Cited By ~ 1

Author(s):

J.W. Steinke ◽

P. Huyett ◽

L. Borish

Keyword(s):

Arachidonic Acid ◽

Mast Cells ◽

Signaling Pathway ◽

Arachidonic Acid Metabolites ◽

Acid Metabolites

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IL-13 induces serine phosphorylation of cPLA2 in mouse peritoneal macrophages leading to arachidonic acid and PGE2 production and blocks the zymosan-induced serine phosphorylation of cPLA2 and eicosanoid production

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ◽

10.1016/s1388-1981(99)00121-3 ◽

1999 ◽

Vol 1440 (2-3) ◽

pp. 183-193 ◽

Cited By ~ 9

Author(s):

Astrid Rey ◽

Fabio Quartulli ◽

Laure Escoubet ◽

Patricia Sozzani ◽

Daniel Caput ◽

...

Keyword(s):

Arachidonic Acid ◽

Peritoneal Macrophages ◽

Serine Phosphorylation ◽

Pge2 Production ◽

Eicosanoid Production ◽

Mouse Peritoneal Macrophages

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The immediate phase of c-kit ligand stimulation of mouse bone marrow-derived mast cells elicits rapid leukotriene C4 generation through posttranslational activation of cytosolic phospholipase A2 and 5-lipoxygenase.

Journal of Experimental Medicine ◽

10.1084/jem.182.1.197 ◽

1995 ◽

Vol 182 (1) ◽

pp. 197-206 ◽

Cited By ~ 86

Author(s):

M Murakami ◽

K F Austen ◽

J P Arm

Keyword(s):

Bone Marrow ◽

Arachidonic Acid ◽

Mast Cells ◽

Cell Membrane ◽

Phospholipase A2 ◽

Mouse Bone Marrow ◽

Kit Ligand ◽

Cytosolic Phospholipase ◽

Delayed Phase ◽

Stimulation Of

c-kit ligand (KL) activated mouse bone marrow-derived mast cells (BMMC) for the dose- and time-dependent release of arachidonic acid from cell membrane phospholipids, with generation of leukotriene (LT) C4 in preference to prostaglandin (PG)D2. KL at concentrations of 10 ng/ml elicited half-maximal eicosanoid generation and at concentrations of > 50 ng/ml elicited a maximal generation of approximately 15 ng LTC4 and 1 ng PGD2 per 10(6) cells, with 20% net beta-hexosaminidase release 10 min after stimulation. Of the other cytokines tested, none, either alone or in combination with KL, elicited or modulated the immediate phase of mediator release by BMMC, indicating strict specificity for KL. Activation of BMMC in response to KL was accompanied by transient phosphorylation of cytosolic phospholipase A2 and reversible translocation of 5-lipoxygenase to a cell membrane fraction 2-5 min after stimulation, when the rate of arachidonic acid release and LTC4 production were maximal. BMMC continuously exposed to KL in the presence of IL-10 and IL-1 beta generated LTC4 in marked preference to PGD2 over the first 10 min followed by delayed generation of PGD2 with no LTC4 over several hours. Pharmacologic studies revealed that PGD2 generation in the immediate phase depended on prostaglandin endoperoxide synthase (PGHS)-1 and in the delayed phase on PGHS-2. Thus, KL provided a nonallergic stimulus for biphasic eicosanoid generation by mast cells. The immediate phase is dominated by LTC4 generation with kinetics and postreceptor biosynthetic events similar to those observed after cell activation through the high affinity IgE receptor, whereas the delayed phase of slow and selective PGD2 production is mediated by induction of PGHS-2.

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Migration of human inflammatory cells into the lung results in the remodeling of arachidonic acid into a triglyceride pool.

Journal of Experimental Medicine ◽

10.1084/jem.182.5.1181 ◽

1995 ◽

Vol 182 (5) ◽

pp. 1181-1190 ◽

Cited By ~ 62

Author(s):

M Triggiani ◽

A Oriente ◽

M C Seeds ◽

D A Bass ◽

G Marone ◽

...

Keyword(s):

Arachidonic Acid ◽

Mast Cells ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Adult Respiratory Distress Syndrome ◽

Distress Syndrome ◽

Inflammatory Cells ◽

Lipid Bodies ◽

Blood Neutrophils ◽

High Concentrations

Increasing evidence suggests that the metabolism of arachidonic acid (AA) may be different in inflammatory cells isolated from blood or migrating into tissues. To explore the possibility that changes in AA metabolism between blood and tissue inflammatory cells could be due in part to a different content or distribution of AA in glycerolipid classes, we studied these parameters in six human inflammatory cells isolated from blood (eosinophils, monocytes, neutrophils, and platelets) or from the lung tissue (mast cells and macrophages). Lung cells generally had a higher total cellular content of AA than that found in the blood cells. In addition, both mast cells and macrophages had a large endogenous pool of AA associated with triglycerides (TG), containing 45 and 22% of their total cellular AA, respectively. To address the hypothesis that cells migrating into the lung had a higher cellular level of AA and a larger AA pool in TG, we studied neutrophils isolated from the bronchoalveolar lavage (BAL) of patients with adult respiratory distress syndrome. BAL neutrophils had a fourfold increase in cellular AA as compared with blood neutrophils and contained 25% of their AA in TG versus 3% in blood neutrophils. BAL neutrophils also had a higher number of cytoplasmic lipid bodies (8 +/- 3/cell) relative to blood neutrophils (2 +/- 1/cell). High concentrations of free AA were also found in the cell-free BAL fluid of adult respiratory distress syndrome patients. To explore whether changes in BAL neutrophils may be due to the exposure of the cells to high concentrations of exogenous AA found in BAL, we incubated blood neutrophils in culture with AA (10-100 microM) for 24 h. Neutrophils supplemented with AA had a 10-fold increase in the amount of AA associated with TG and a sixfold increase in the number of lipid bodies. In addition, supplementation with AA induced a dose-dependent formation of hypodense cells. Taken together, these data indicate that human inflammatory cells undergo a fundamental and consistent remodeling of AA pools as they mature or enter the lung from the blood. These biochemical and morphological changes can be mimicked in vitro by exposing the cells to high levels of AA. This mechanism may be responsible for the changes in AA mobilization and eicosanoid metabolism observed in tissue inflammatory cells.

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