Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation

Lordén, Gema; Sanjuán-García, Itziar; Pablo, Nagore de; Meana, Clara; Álvarez-Miguel, Inés; Pérez-Garcı́a, M. Teresa; Pelegrı́n, Pablo; Balsinde, Jesús; Balboa, Marı́a A.

doi:10.1084/jem.20161452

Cited by 96 publications

(119 citation statements)

References 50 publications

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“…Osteomyelitis in lipin 2-deficient humans occurs episodically in response to unknown metabolic stressors, which laboratory mice presumably do not experience. Recent work has identified lipin 2 as a regulator of NLRP3 inflammasome activation [119]. Lipin 2 influences MAP kinase signaling to regulate interleukin (IL)-1β production during inflammasome priming.…”

Section: Mouse Models To Study the Physiology Of Glycerolipid Metabmentioning

confidence: 99%

“…Lipin 2 influences MAP kinase signaling to regulate interleukin (IL)-1β production during inflammasome priming. Lipin 2 knockdown in human macrophages led to enhanced IL-1β production, as is observed in Majeed syndrome [119]. Lipin 2-deficient mice injected with high doses of lipopolysaccharide had an exaggerated response, producing high levels of inflammatory cytokines (IL-1β, IL-18, tumor necrosis factor α), and reduced expression of anti-inflammatory cytokines (IL-10) [119].…”

Section: Mouse Models To Study the Physiology Of Glycerolipid Metabmentioning

confidence: 99%

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How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

Wang

Airola

Reue

2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Triacylglycerols (TAG) serve as the predominant form of energy storage in mammalian cells, and TAG synthesis influences conditions such as obesity, fatty liver, and insulin resistance. In most tissues, the glycerol 3-phosphate pathway enzymes are responsible for TAG synthesis, and the regulation and function of these enzymes is therefore important for metabolic homeostasis. Here we review the sites and regulation of glycerol-3-phosphate acyltransferase (GPAT), acylglycerol-3-phosphate acyltransferase (AGPAT), lipin/phosphatidic acid phosphatase (PAP), and diacylglycerol acyltransferase (DGAT) enzyme action. We highlight the critical roles that these enzymes play in human health by reviewing Mendelian disorders that result from mutation in the corresponding genes. We also summarize the valuable insights that genetically engineered mouse models have provided into the cellular and physiological roles of GPATs, AGPATs, lipins and DGATs. Finally, we comment on the status and feasibility of therapeutic approaches to metabolic disease that target enzymes of the glycerol 3-phosphate pathway.

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Section: Mouse Models To Study the Physiology Of Glycerolipid Metabmentioning

confidence: 99%

Section: Mouse Models To Study the Physiology Of Glycerolipid Metabmentioning

confidence: 99%

How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

Wang

Airola

Reue

2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…Until recently, the role of LIPIN2 in inflammation was unknown, however, two groups recently reported findings that demonstrate the importance of LIPIN2 in inflammation(40, 41). LIPIN2 is a phosphatidic acid phosphatase (PAP) that plays an important role in triglyceride synthesis and dephosphorylation of phosphatidic acid (PA) to generate diacylglycerol (34, 42–44).…”

Section: Majeed Syndrome and Lpin2mentioning

confidence: 99%

Chronic Recurrent Multifocal Osteomyelitis and Related Diseases—Update on Pathogenesis

2017

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Purpose of the review We focus on recent advances in the understanding of the genetic, molecular, immunologic and environmental factors implicated in the pathogenesis of autoinflammatory bone diseases including the syndromic and non-syndromic forms of chronic recurrent multifocal osteomyelitis (CRMO). Recent findings Evidence implicating the IL-1 pathway in the pathogenesis of the Mendelian forms of CRMO is growing. LIPIN2 can regulate the NLRP3 inflammasome by affecting P2×7 receptor activation and intracellular cholesterol can modulate P2×7R currents. Work in a mouse model of CRMO demonstrates that dietary manipulation can alter the microbiome and protect these mice from the development of sterile osteomyelitis in vivo. Summary Although the genetic and immunologic basis of non-syndromic CRMO remains only partially understood, the IL-1 pathway is central to the pathogenesis in the syndromic autoinflammatory bone disorders. Recent work implicates lipids and the microbiome in sterile osteomyelitis.

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“…In macrophages, reduced levels of lipin-2 cause a decrease of cell cholesterol levels. In conclusion, lipin-2 is able to down-regulate NLRP3 inflammasome (91). …”

Section: Introductionmentioning

confidence: 98%

“…Later, in 2015, a diagnosis of CANDLE syndrome was performed by targeted sequencing of one 3-year-old CANDLE syndrome Hispanic male patient, born to consanguineous healthy parents. A homozygous c.280G>C, p.A94P mutation in PSMB8 gene was not observed in any public genetic databases and was predicted to be pathogenic by several prediction tools (91). …”

Section: Introductionmentioning

confidence: 99%

Monogenic Autoinflammatory Diseases with Mendelian Inheritance: Genes, Mutations, and Genotype/Phenotype Correlations

et al. 2017

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Autoinflammatory diseases (AIDs) are a genetically heterogeneous group of diseases caused by mutations of genes encoding proteins, which play a pivotal role in the regulation of the inflammatory response. In the pathogenesis of AIDs, the role of the genetic background is triggered by environmental factors through the modulation of the innate immune system. Monogenic AIDs are characterized by Mendelian inheritance and are caused by highly penetrant genetic variants in single genes. During the last years, remarkable progress has been made in the identification of disease-associated genes by using new technologies, such as next-generation sequencing, which has allowed the genetic characterization in undiagnosed patients and in sporadic cases by means of targeted resequencing of a gene panel and whole exome sequencing. In this review, we delineate the genetics of the monogenic AIDs, report the role of the most common gene mutations, and describe the evidences of the most sound genotype/phenotype correlations in AID.

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Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation

Abstract: Lordén et al. show that the phosphatidic acid phosphatase lipin-2 is a key regulator of the cellular machinery that generates IL-1β in macrophages. This work provides a molecular explanation for the development of the autoinflammatory disease known as Majeed syndrome.

Cited by 96 publications

References 50 publications

How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

Chronic Recurrent Multifocal Osteomyelitis and Related Diseases—Update on Pathogenesis

Monogenic Autoinflammatory Diseases with Mendelian Inheritance: Genes, Mutations, and Genotype/Phenotype Correlations

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