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Stamp2 controls macrophage inflammation through nicotinamide adenine dinucleotide phosphate homeostasis and protects against atherosclerosis.

ABSTRACT: The six-transmembrane protein Stamp2 plays an important role in metabolically triggered inflammation and insulin action. We report that Stamp2 is expressed in human and mouse macrophages, is regulated upon differentiation or activation, acts as an anti-inflammatory protein, and regulates foam cell formation. Absence of Stamp2 results in significant increases in cellular NADPH levels, and both NADPH homeostasis and the exaggerated inflammatory response of Stamp2(-/-) macrophages are rescued by exogenous wild-type but not by a reductase-deficient Stamp2 molecule. Chemical and genetic suppression of NADPH production in Stamp2(-/-) macrophages reverts the heightened inflammatory response. Stamp2 is detected in mouse and human atherosclerotic plaques, and its deficiency promotes atherosclerosis in mice. Furthermore, bone marrow transplantation experiments demonstrated that Stamp2 in myeloid cells is sufficient to protect against atherosclerosis. Our data reveal a role of Stamp2 in controlling intermediary metabolites to regulate inflammatory responses in macrophages and in progression of atherosclerosis.

SUBMITTER: ten Freyhaus H

PROVIDER: S-EPMC4163924 | biostudies-other | 2012 Jul

REPOSITORIES: biostudies-other

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Stamp2 controls macrophage inflammation through nicotinamide adenine dinucleotide phosphate homeostasis and protects against atherosclerosis.

ten Freyhaus Henrik H Calay Ediz S ES Yalcin Abdullah A Vallerie Sara N SN Yang Ling L Calay Zerrin Z ZZ Saatcioglu Fahri F Hotamisligil Gökhan S GS

Cell metabolism 20120614 1

The six-transmembrane protein Stamp2 plays an important role in metabolically triggered inflammation and insulin action. We report that Stamp2 is expressed in human and mouse macrophages, is regulated upon differentiation or activation, acts as an anti-inflammatory protein, and regulates foam cell formation. Absence of Stamp2 results in significant increases in cellular NADPH levels, and both NADPH homeostasis and the exaggerated inflammatory response of Stamp2(-/-) macrophages are rescued by ex ...[more]

PMID: 22704678

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Project description:ObjectiveWe previously demonstrated that nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) mediates increased monocyte priming and chemotaxis under conditions of diabetic metabolic stress, and emerging data indicate that group VIA phospholipase A2 (iPLA2β) also participates in regulating monocyte chemotaxis. Here, we examined relationships between iPLA2β expression and Nox4 action in mouse peritoneal macrophages subjected to diabetic metabolic stress.Approach and resultsIncreased iPLA2β expression and activity were observed in macrophages from low-density lipoprotein receptor knockout mice that were fed a high-fat diet, and this was associated with time-dependent increases in atherosclerotic lesion size and macrophage content. Incubating macrophages with 30 mmol/L D-glucose, 100 μg/mL low-density lipoprotein, or both (D-glucose+low-density lipoprotein) induced a robust increase in iPLA2β expression and activity and in cell migration in response to monocyte chemoattractant protein-1. The increases in iPLA2β activity and cell migration were prevented by a bromoenol lactone iPLA2β suicide inhibitor or an iPLA2β antisense oligonucleotide. Incubating macrophages under conditions that mimic diabetic metabolic stress ex vivo resulted in increased Nox4 expression and activity and hydrogen peroxide generation compared with controls. Bromoenol lactone prevented those effects without affecting Nox2 expression. Nox4 inhibition eliminated diabetic metabolic stress-induced acceleration of macrophage migration. Lysophosphatidic acid restored Nox4 expression, hydrogen peroxide generation, and migration to bromoenol lactone-treated cells, and a lysophosphatidic acid receptor antagonist abrogated iPLA2β-mediated increases in Nox4 expression.ConclusionsTaken together, these observations identify iPLA2β and lysophosphatidic acid derived from its action as critical in regulating macrophage Nox4 activity and migration in the diabetic state in vivo and under similar conditions ex vivo.

Dataset Information

Stamp2 controls macrophage inflammation through nicotinamide adenine dinucleotide phosphate homeostasis and protects against atherosclerosis.

Publications

Stamp2 controls macrophage inflammation through nicotinamide adenine dinucleotide phosphate homeostasis and protects against atherosclerosis.

Similar Datasets

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