Stamp2 controls macrophage inflammation through nicotinamide adenine dinucleotide phosphate homeostasis and protects against atherosclerosis.
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.
Department of Genetics, Harvard School of Public Health, Boston, MA 02115, USA.
Henrik
H
ten Freyhaus
Ediz S
ES
Calay
Abdullah
A
Yalcin
Sara N
SN
Vallerie
Ling
L
Yang
Zerrin Z
ZZ
Calay
Fahri
F
Saatcioglu
Gökhan S
GS
Hotamisligil
D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D005260:Female; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009249:NADP / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism
D001057:Apolipoproteins E; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C436323:Tiarp protein, mouse; D009249:NADP; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse