Nature Medicine11, 666 - 671 (2005)
Published online: 15 May 2005; | doi:10.1038/nm1248
Inflammatory arthritis requires Foxo3a to prevent Fas ligand−induced neutrophil apoptosis
Helena Jonsson1, Paul Allen2
& Stanford L Peng1, 2
1
Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri
63110, USA.
2
Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri
63110, USA.
Correspondence should be addressed to Stanford L Peng speng@im.wustl.edu
In inflammatory arthridities such as rheumatoid arthritis, cognate lymphocytes have long been considered instigators of autoimmunity, but accumulating evidence indicates that innate immune cells such as neutrophils and mast cells are responsible for a vast majority of acute and ongoing inflammation1,
2,
3; however, the molecular mechanisms that govern them remain largely unknown. Here we show that such inflammation requires the forkhead transcription factor Foxo3a: Foxo3a-deficient mice are resistant to two models of neutrophilic inflammation, immune complex−mediated inflammatory arthritis and thioglycollate-induced peritonitis. This reflects a need for Foxo3a to maintain neutrophil vitality during inflammation by suppressing Fas ligand; because Foxo3a can bind and suppress the Fasl promoter, Foxo3a-deficient neutrophils upregulate Fas ligand and undergo apoptosis in response to TNF- and IL-1, and Fas ligand blockade renders Foxo3a-deficient mice susceptible to both arthritis and peritonitis. Thus, Foxo3a ensures neutrophil survival during inflammation, identifying Foxo3a as therapeutic target in inflammation.
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and IL-1, and Fas ligand blockade renders Foxo3a-deficient mice susceptible to both arthritis and peritonitis. Thus, Foxo3a ensures neutrophil survival during inflammation, identifying Foxo3a as therapeutic target in inflammation.
