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Inflammatory arthritis requires Foxo3a to prevent Fas ligand–induced neutrophil apoptosis

Abstract

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-α 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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Figure 1: Foxo3a-deficient mice resist K/BxN serum transfer arthritis as a result of an intrinsic neutrophil defect.
Figure 2: Thioglycollate-induced neutrophilic peritoneal inflammation requires Foxo3a to prevent FasL-induced apoptosis.
Figure 3: Foxo3a protects against neutrophilic FasL-induced apoptosis in inflammatory arthritis.
Figure 4: Fas1 is a negatively regulated Foxo3a target gene.

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Acknowledgements

We thank C. Pham for review of the manuscript. This work was supported in part by the Rheumatic Disease, Siteman Cancer, Diabetes Research and Training and the Digestive Diseases Research Core (DK52574) Centers of the Washington University School of Medicine, as well as grants from the US National Institutes of Health (AI057471 and AI061478 to S.L.P.), the Arthritis Foundation and the Lupus Research Institute. S.L.P. is supported in part by an Arthritis Investigator Award from the Arthritis Foundation.

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Correspondence to Stanford L Peng.

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Supplementary information

Supplementary Fig. 1

Intra-articular inflammatory cytokine expression during arthritis in the absence of Foxo3a. (PDF 25 kb)

Supplementary Fig. 2

Rag-2 deficiency does not alter the resistance of Foxo3a KO animals to K/BxN serum transfer arthritis. (PDF 34 kb)

Supplementary Fig. 3

Foxo3a expression in mouse neutrophils. (PDF 22 kb)

Supplementary Fig. 4

Entry of WT neutrophils into the joints of Foxo3a KO mice. (PDF 37 kb)

Supplementary Fig. 5

Analysis of potential target genes in Foxo3a-deficient neutrophils. (PDF 133 kb)

Supplementary Table 1

Characteristics of immune complex arthritis in the absence of Foxo3a. (PDF 21 kb)

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Jonsson, H., Allen, P. & Peng, S. Inflammatory arthritis requires Foxo3a to prevent Fas ligand–induced neutrophil apoptosis. Nat Med 11, 666–671 (2005). https://doi.org/10.1038/nm1248

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