The exogenous lipid requirement for histamine release from rat peritoneal mast cells stimulated by concanavalin A

Smith, Gavin; Hesketh, T R; Plumb, Rachel; Metcalfe, J. C.

doi:10.1016/0014-5793(79)80887-x

Cited by 55 publications

(32 citation statements)

References 13 publications

(3 reference statements)

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“…LPS has been shown to be a bioactive lipid that produces several cellular effects (14), including mast cell degranulation (15)(16)(17), macrophage clearance of apoptotic cells (18,19), leukemic cell stimulation (20), and chemotactic migration of human glioma cells (21) and murine fibroblasts (22). Although the bioactivity of LPS in the nervous system has not been well studied, our findings support a model where LPS exhibits similar immunomodulatory activities to stimulate microglial function in the brain.…”

Section: Discussionsupporting

confidence: 73%

ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC

Blankman

Long

Trauger

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

165

279

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Advances in human genetics are leading to the discovery of new disease-causing mutations at a remarkable rate. Many such mutations, however, occur in genes that encode for proteins of unknown function, which limits our molecular understanding of, and ability to devise treatments for, human disease. Here, we use untargeted metabolomics combined with a genetic mouse model to determine that the poorly characterized serine hydrolase α/β-hydrolase domain-containing (ABHD)12, mutations in which cause the human neurodegenerative disorder PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, and cataract), is a principal lysophosphatidylserine (LPS) lipase in the mammalian brain. ABHD12 −/− mice display massive increases in a rare set of very long chain LPS lipids that have been previously reported as Toll-like receptor 2 activators. We confirm that recombinant ABHD12 protein exhibits robust LPS lipase activity, which is also substantially reduced in ABHD12 −/− brain tissue. Notably, elevations in brain LPS lipids in ABHD12 −/− mice occur early in life (2-6 mo) and are followed by age-dependent increases in microglial activation and auditory and motor defects that resemble the behavioral phenotypes of human PHARC patients. Taken together, our data provide a molecular model for PHARC, where disruption of ABHD12 causes deregulated LPS metabolism and the accumulation of proinflammatory lipids that promote microglial and neurobehavioral abnormalities.lipidomics | neuroinflammation G enome mapping and sequencing have facilitated determination of the genetic basis for over 3,500 inherited diseases in humans (1), with additional pathogenic mutations still being discovered. For many Mendelian disorders, however, the molecular and cellular mechanisms that link genotype to disease phenotype remain poorly understood. This problem is perhaps most apparent for diseases where the causative mutations occur in genes that encode for proteins with unannotated or poorly characterized functions. Here, we focus on one such disease -the neurodegenerative disorder PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, and cataract).PHARC [Mendelian Inheritance in Man (MIM) no. 612674; Online Mendelian Inheritance in Man database, http://omim.org] is a rare, autosomal recessive disorder that causes polymodal sensory and motor defects associated with demyelination of sensomotor neurons, retinal dystrophy, and cerebellar atrophy (2). PHARC symptoms are slowly progressive and begin in the childhood or teenage years; heterozygous carriers are unaffected (3). In 2010, PHARC was reported to be caused by homozygous mutations in ABHD12, which codes for the poorly characterized serine hydrolase enzyme α/β-hydrolase domain-containing (ABHD)12 (3). To date, five distinct ABHD12 mutations have been identified in patients with PHARC, all of which are expected to lead to complete loss of ABHD12 expression (3, 4). PHARC, therefore, likely represents a human ABHD12 null model.We demonstrated previously that ABHD12 is a membranebound e...

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Section: Discussionsupporting

confidence: 73%

ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC

Blankman

Long

Trauger

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

165

279

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“…Lyso-PS Are Abundant Modified PS Species Generated in Neutrophils Stimulated to Activate the NADPH Oxidase-The signaling potential of lyso-PS was first recognized in its description as a potent mast cell secretagogue, and it has subsequently been given signaling roles in other settings (20,21,39,55,56). Here, we have shown that lyso-PS species were generated in vitro and in vivo as major modified PS species in neutrophils stimulated to activate the NADPH oxidase.…”

Section: Discussionmentioning

confidence: 71%

NADPH Oxidase-dependent Generation of Lysophosphatidylserine Enhances Clearance of Activated and Dying Neutrophils via G2A

Frasch

Berry

Fernandez-Boyanapalli

et al. 2008

Journal of Biological Chemistry

102

141

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Exofacial phosphatidylserine (PS) is an important ligand mediating apoptotic cell clearance by phagocytes. Oxidation of PS fatty acyl groups (oxPS) during apoptosis reportedly mediates recognition through scavenger receptors. Given the oxidative capacity of the neutrophil NADPH oxidase, we sought to identify oxPS signaling species in stimulated neutrophils. Using mass spectrometry analysis, only trace amounts of previously characterized oxPS species were found. Conversely, 18:1 and 18:0 lysophosphatidylserine (lysoPS), known bioactive signaling phospholipids, were identified as abundant modified PS species following activation of the neutrophil oxidase. NADPH oxidase inhibitors blocked the production of lyso-PS in vitro, and accordingly, its generation in vivo by activated, murine neutrophils during zymosan-induced peritonitis was absent in mice lacking a functional NADPH oxidase (gp91 phox؊/؊ ). Treatment of macrophages with lyso-PS enhanced the uptake of apoptotic cells in vitro, an effect that was dependent on signaling via the macrophage G2A receptor. Similarly, endogenously produced lyso-PS also enhanced the G2A-mediated uptake of activated PS-exposing (but non-apoptotic) neutrophils, raising the possibility of non-apoptotic mechanisms for removal of inflammatory cells during resolution. Finally, antibody blockade of G2A signaling in vivo prolonged zymosan-induced neutrophilia in wild-type mice, whereas having no effect in gp91 phox؊/؊ mice where lyso-PS are not generated. Taken together, we show that lyso-PS are modified PS species generated following activation of the NADPH oxidase and lyso-PS signaling through the macrophage G2A functions to enhance existing receptor/ligand systems for optimal resolution of neutrophilic inflammation.Neutrophils are often robustly recruited early in inflammation. Within hours of their activation in tissues, they are removed by phagocytes, an event required for resolution of inflammation and the return to normalcy of tissue function. It is known that neutrophils undergoing apoptosis drive the production of anti-inflammatory mediators such as transforming growth factor-␤ that actively suppress production of inflammatory cytokines, chemokines, eicosanoids, and nitric oxide (1, 2). Indeed, enhanced induction of neutrophil apoptosis in vivo is potently anti-inflammatory (3, 4). However, if recognition and clearance fail, activated and dying neutrophils ultimately disintegrate releasing injurious intracellular constituents (e.g. serine proteases) (5). Failure of timely cell clearance is associated with both autoimmunity and enhanced inflammation (6, 7).Phosphatidylserine (PS) 2 exposed in the plasma membrane outer leaflet of apoptotic cells has long been known as a key ligand important for their recognition and removal. Interaction with various PS receptors, including the recently identified TIM4 (8, 9), BAI1 (10), and stabilin 2 (11) or PS-recognizing bridge molecule-receptor combinations (e.g. MFG-E8 and ␣ v integrins or Gas6 and Mer (12)), have been demonstrated. In many, bu...

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“…1C). PS-PLA 1 produces LPS from PS (24,46), a potential lysophospholipid mediator with an activity to stimulate mast cell degranulation (47,48) and neurite outgrowth (27). Recently we showed (25) that PS-PLA 1 also functions as a synthetic enzyme of LPS.…”

Section: Discussionmentioning

confidence: 99%

A Novel Phosphatidic Acid-selective Phospholipase A1That Produces Lysophosphatidic Acid

Sonoda

Aoki

Hiramatsu

et al. 2002

Journal of Biological Chemistry

192

182

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Lysophosphatidic acid (LPA) is a lipid mediator with diverse biological properties, although its synthetic pathways have not been completely solved. We report the cloning and characterization of a novel phosphatidic acid (PA)-selective phospholipase A 1 (PLA 1 ) that produces 2-acyl-LPA. The PLA 1 was identified in the GenBank TM data base as a close homologue of phosphatidylserine (PS)-specific PLA 1 (PS-PLA 1 ). When expressed in insect Sf9 cells, this enzyme was recovered from the Triton X-100-insoluble fraction and did not show any catalytic activity toward exogenously added phospholipid substrates. However, culture medium obtained from Sf9 cells expressing the enzyme was found to activate EDG7/LPA 3 , a cellular receptor for 2-acyl-LPA. The activation of EDG7 was further enhanced when the cells were treated with phorbol ester or a bacterial phospholipase D, suggesting involvement of phospholipase D in the process. In the latter condition, an increased level of LPA, but not other lysophospholipids, was confirmed by mass spectrometry analyses. Expression of the enzyme is observed in several human tissues such as prostate, testis, ovary, pancreas, and especially platelets. These data show that the enzyme is a membrane-associated PA-selective PLA 1 and suggest that it has a role in LPA production.

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The exogenous lipid requirement for histamine release from rat peritoneal mast cells stimulated by concanavalin A

Cited by 55 publications

References 13 publications

ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC

ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC

NADPH Oxidase-dependent Generation of Lysophosphatidylserine Enhances Clearance of Activated and Dying Neutrophils via G2A

A Novel Phosphatidic Acid-selective Phospholipase A1That Produces Lysophosphatidic Acid

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