Macrophage beta3 integrin suppresses hyperlipidemia-induced inflammation by modulating TNFalpha expression.
Arterioscler Thromb Vasc Biol
; 27(12): 2699-706, 2007 Dec.
Article
en En
| MEDLINE
| ID: mdl-17951320
ABSTRACT
OBJECTIVE:
High-fat, cholesterol-containing diets contribute to hyperlipidemia. Both high-fat diets and hyperlipidemia are associated with chronic inflammatory diseases like atherosclerosis. Integrins, heterodimeric mediators of inflammatory cell recruitment, are not generally thought to be affected by diet. However, high-fat feeding promotes inflammation, atherosclerosis, and death in hyperlipidemic mice with beta3 integrin deficiency, and treatment of humans from Western populations with oral beta3 integrin inhibitors increases mortality. The mechanisms responsible for these beta3 integrin-associated events are unknown. METHODS ANDRESULTS:
Here we show that diet-induced death in beta3 integrin-deficient mice is a TNFalpha-dependent process mediated by bone marrow-derived cells. In 2 different hyperlipidemic models, apoE-null and LDL receptor-null mice, beta3-replete animals transplanted with beta3-deficient marrow died with Western-type high-fat feeding whereas beta3-deficient animals transplanted with beta3-replete marrow were rescued from diet-induced death. Transplantation with beta3-deficient marrow also increased atherosclerosis. TNFalpha [corrected] expression was increased in beta3-deficient macrophages and normalized by either retroviral or adenoviral reconstitution of beta3 integrin expression. Treatment with the anti-TNFalpha antibody infliximab rescued beta3 integrin-deficient mice from Western diet-induced death, directly implicating TNFalpha in the pathophysiology triggered by diet-induced hyperlipidemia.CONCLUSIONS:
These findings suggest that macrophage beta3 integrin, acting through TNFalpha, suppresses inflammation caused by hyperlipidemia attributable to high-fat feeding.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Factor de Necrosis Tumoral alfa
/
Integrina beta3
/
Aterosclerosis
/
Hiperlipidemias
/
Inflamación
/
Macrófagos
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Asunto de la revista:
ANGIOLOGIA
Año:
2007
Tipo del documento:
Article
País de afiliación:
Estados Unidos