12/15-Lipoxygenase (LOX) mediates immune-regulatory activities not accounted for by its known free acid eicosanoids, suggesting that additional lipids may be generated by activated cells. To characterize novel LOX-derived lipids, a lipidomic approach was utilized. Ionophore-activated interleukin-4-treated human peripheral monocytes generated up to 10-fold more esterified 15-hydroxyeicosatetraenoic acid (15-HETE) than free in a phosphatidylinositol 3-kinase-and protein kinase C-sensitive manner. Precursor scanning electrospray ionization/tandem spectroscopy for m/z 319 (HETE, [M-H] ؊ ) showed 4 ions at m/z 738, 764, 766, and 782 that were identified using tandem spectroscopy and MS3 as specific diacyl and plasmalogen 15-HETE phosphatidylethanolamines. Using H 2 18 O water, the compounds were shown to form by direct oxidation of endogenous phosphatidylethanolamine (PE) by 15-LOX, with PE being the preferred phospholipid pool containing 15-HETE. Similarly, human platelets generated 4 analogous PE lipids that contained 12-HETE and increased significantly in response to ionophore, collagen, or convulxin. These products were retained in the cells, in contrast to free acids, which are primarily secreted. Precursor scanning of platelet extracts for the major platelet-derived prostanoid, thromboxane B2 (m/z 369.2), did not reveal PE esters, indicating that this modification is restricted to the LOX pathway. In summary, we show formation of PE-esterified HETEs in immune cells that may contribute to LOX signaling in inflammation.
While investigating new mechanisms by which the dietary omega-3 fatty acids regulate inflammation, the authors have identified a new step in the regulation of neutrophil migration across vascular endothelial cells.
The peritoneal macrophage (Mφ) is the site of greatest 12/15-lipoxygenase (12/15-LOX) expression in the mouse; however, its immunoregulatory role in this tissue has not been explored. Herein, we show that 12/15-LOX is expressed by 95% of resident peritoneal CD11bhigh cells, with the remaining 5% being 12/15-LOX−. 12/15-LOX+ cells are phenotypically defined by high F4/80, SR-A, and Siglec1 expression, and enhanced IL-10 and G-CSF generation. In contrast, 12/15-LOX− cells are a dendritic cell population. Resident peritoneal Mφ numbers were significantly increased in 12/15-LOX−/− mice, suggesting alterations in migratory trafficking or cell differentiation in vivo. In vitro, Mφ from 12/15-LOX−/− mice exhibit multiple abnormalities in the regulation of cytokine/growth factor production both basally and after stimulation with Staphylococcus epidermidis cell-free supernatant. Resident adherent cells from 12/15-LOX−/− mice generate more IL-1, IL-3, GM-CSF, and IL-17, but less CCL5/RANTES than do cells from wild-type mice, while Staphylococcus epidermidis cell-free supernatant-elicited 12/15-LOX−/− adherent cells release less IL-12p40, IL-12p70, and RANTES, but more GM-CSF. This indicates a selective effect of 12/15-LOX on peritoneal cell cytokine production. In acute sterile peritonitis, 12/15-LOX+ cells and LOX products were cleared, then reappeared during the resolution phase. The peritoneal lavage of 12/15-LOX−/− mice showed elevated TGF-β1, along with increased immigration of monocytes/Mφ, but decreases in several cytokines including RANTES/CCL5, MCP-1/CCL2, G-CSF, IL-12-p40, IL-17, and TNF-α. No changes in neutrophil or lymphocyte numbers were seen. In summary, endogenous 12/15-LOX defines the resident MΦ population and regulates both the recruitment of monocytes/Mφ and cytokine response to bacterial products in vivo.
Alternatively activated macrophages (AAM) are a major component of the response to helminth infection; however, their functions remain poorly defined. To better understand the helminth-induced AAM phenotype, we performed a systems-level analysis of in vivo derived AAM using an established mouse model. With next-generation RNA sequencing, we characterized the transcriptomes of peritoneal macrophages from BALB/c and IL4R / mice elicited by the nematode Brugia malayi, or via intraperitoneal thio-glycollate injection. We defined expression profiles of AAM-associated cyto-kines, chemokines, and their receptors, providing evidence that AAM contribute toward recruitment and maintenance of eosinophilia. Pathway analysis highlighted complement as a potential AAM-effector function. Up-regulated mitochon-drial genes support in vitro evidence associating mitochondrial metabolism with alternative activation. We mapped macrophage transcription start sites, defining over-represented cis-regulatory motifs within AAM-associated promoters. These included the binding site for PPAR transcription factors, which maintain mitochondrial metabolism. Surprisingly PPAR, implicated in the maintenance of AAM, was down-regulated on infection. PPAR expression, however, was maintained. To explain how PPAR-mediated transcriptional activation could be maintained, we used lipidomics to quantify AAM-derived eicosanoids, potential PPAR ligands. We identified the PPAR ligand PGI 2 as the most abundant AAM-derived eicosanoid and propose a PGI 2-PPAR axis maintains AAM during B malayi implantation. (Blood. 2012; 120(25):e93-e104)
Abstract-The inflammatory response is an integral part of the innate immune mechanism that is triggered in response to a real or perceived threat to tissue homeostasis, with a primary aim of neutralizing infectious agents and initiating repair to damaged tissue. By design, inflammation is a finite process that resolves as soon as the threat of infection abates and sufficient repair to the tissue is complete. Resolution of inflammation involves apoptosis and subsequent clearance of activated inflammatory cells -a tightly regulated event. Chronic inflammation is a characteristic feature in virtually all inflammatory diseases, including atherosclerosis, and it is becoming increasingly clear that derangement of the processes usually involved in resolution of inflammation is an underlying feature of chronic inflammatory conditions. This review will draw on evidence from a range of diseases in which dysregulated inflammation is important, with particular emphasis on cardiovascular disease. (Arterioscler Thromb Vasc Biol. 2011;31:1001-1006.)Key Words: atherosclerosis Ⅲ eicosanoids Ⅲ lipids Ⅲ NO Ⅲ resolution of inflammation I nflammation is a primary component of the immune system that is triggered by any stimulus that poses a real or perceived threat to tissue homeostasis. 1 The acute inflammatory process is characterized by rapid recruitment of granulocytes (ie, neutrophils, eosinophils, and basophils) to the inflammatory site; the relative contribution of these cell types is dependent on the location of the inflammatory site in question. The migration of granulocytes to inflammatory loci is a necessary requirement for the neutralization and removal of deleterious agents; these cells play a key role in the defense against bacterial, fungal, and viral infections and in resistance to parasitic invasion and the allergic response. Resolution of inflammation is perceived to occur by elimination of granulocytes and the eventual return of tissue mononuclear cell (macrophage and lymphocyte) numbers to basal levels. 2 For effective resolution to occur, cessation of proinflammatory signaling is a prerequisite that pre-empts removal of infiltrating granulocytes. During spontaneous resolution, neutrophils undergo apoptosis, a highly regulated cell death mechanism that prevents the release of histotoxic cellular contents. 3 Alterations in neutrophil cell surface markers and morphological changes during apoptosis correlate with increased recognition by professional phagocytes, such as macrophages, that mediate effective clearance of dying cells. 3,4 It is accepted that the resolution process is active, rather than passive, and is controlled by a range of tightly regulated biochemical and cellular mechanisms. 2 The acute inflammatory response is self-limiting and normally results in tissue restoration and the return of tissue homeostasis. Persistent inflammatory stimuli or dysregulation of mechanisms of the resolution phase results in chronic inflammation, 2 recognized to be a key underlying factor in the progression of a range of d...
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