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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Firestein, G.S. & Zvaifler, N.J. How important are T cells in chronic rheumatoid synovitis? II. T cell-independent mechanisms from beginning to end. Arthritis Rheum. 46, 298–308 (2002).
Wipke, B.T. & Allen, P.M. Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis. J. Immunol. 167, 1601–1608 (2001).
Lee, D.M. & Weinblatt, M.E. Rheumatoid arthritis. Lancet 358, 903–911 (2001).
Birkenkamp, K.U. & Coffer, P.J. FOXO transcription factors as regulators of immune homeostasis: molecules to die for? J. Immunol. 171, 1623–1629 (2003).
Medema, R.H., Kops, G.J., Bos, J.L. & Burgering, B.M. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404, 782–787 (2000).
Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868 (1999).
Dijkers, P.F. et al. FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B-enhanced cell survival through maintenance of mitochondrial integrity. J. Cell Biol. 156, 531–542 (2002).
Stahl, M. et al. The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J. Immunol. 168, 5024–5031 (2002).
Asselin-Labat, M.L. et al. GILZ, a new target for the transcription factor FoxO3, protects T lymphocytes from interleukin 2 withdrawal-induced apoptosis. Blood 104, 215–223 (2004).
Lin, L., Hron, J.D. & Peng, S.L. Regulation of NF-κB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a. Immunity 21, 203–213 (2004).
Crossley, L.J. Neutrophil activation by fMLP regulates FOXO (forkhead) transcription factors by multiple pathways, one of which includes the binding of FOXO to the survival factor Mcl-1. J. Leukoc. Biol. 74, 583–592 (2003).
Yang, K.Y. et al. Involvement of phosphatidylinositol 3-kinase gamma in neutrophil apoptosis. Cell. Signal. 15, 225–233 (2003).
Kouskoff, V. et al. Organ-specific disease provoked by systemic autoimmunity. Cell 87, 811–822 (1996).
Ji, H. et al. Critical roles for interleukin 1 and tumor necrosis factor α in antibody-induced arthritis. J. Exp. Med. 196, 77–85 (2002).
Matsumoto, I. et al. How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease. Nat. Immunol. 3, 360–365 (2002).
Lee, D.M. et al. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 297, 1689–1692 (2002).
Ji, H. et al. Arthritis critically dependent on innate immune system players. Immunity 16, 157–168 (2002).
Matsumoto, I., Staub, A., Benoist, C. & Mathis, D. Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme. Science 286, 1732–1735 (1999).
Mayadas, T.N., Johnson, R.C., Rayburn, H., Hynes, R.O. & Wagner, D.D. Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice. Cell 74, 541–554 (1993).
Collart, M.A., Belin, D., Vassalli, J.D., de Kossodo, S. & Vassalli, P. a interferon enhances macrophage transcription of the tumor necrosis factor/cachectin, interleukin 1, and urokinase genes, which are controlled by short-lived repressors. J. Exp. Med. 164, 2113–2118 (1986).
Li, P. et al. AKT-independent protection of prostate cancer cells from apoptosis mediated through complex formation between the androgen receptor and FKHR. Mol. Cell. Biol. 23, 104–118 (2003).
Alvarez, B., Martinez-Alvarez, C., Burgering, B.M.T. & Carrera, A.C. Forkhead transcription factors contribute to execution of the mitotic programme in mammals. Nature 413, 744–747 (2001).
Alvarado-Kristensson, M. et al. p38-MAPK signals survival by phosphorylation of caspase-8 and caspase-3 in human neutrophils. J. Exp. Med. 199, 449–458 (2004).
Altznauer, F. et al. Inflammation-associated cell cycle-independent block of apoptosis by survivin in terminally differentiated neutrophils. J. Exp. Med. 199, 1343–1354 (2004).
Norris, J.S. et al. The use of Fas Ligand, TRAIL and Bax in gene therapy of prostate cancer. Curr. Gene Ther. 1, 123–136 (2001).
Villunger, A., O'Reilly, L.A., Holler, N., Adams, J. & Strasser, A. Fas ligand, Bcl-2, granulocyte colony-stimulating factor, and p38 mitogen-activated protein kinase: Regulators of distinct cell death and survival pathways in granulocytes. J. Exp. Med. 192, 647–658 (2000).
Gerth, A.J., Pham, C.T.N. & Peng, S.L. Nuclear factor of activated T cells regulates the symmetry and intensity of immune complex-mediated synovitis. Arthritis Rheum. 50, 3392–3395 (2004).
Luo, Y. & Dorf, M.E. Unit 3.20. Isolation of Mouse Neutrophils. in Current Protocols in Immunology (eds. Coligan, J.E., Margulies, D.H., Shevach, E.M. & Strober, W.) (John Wiley & Sons, Inc., Philadelphia, 1997).
Gerth, A.J., Lin, L. & Peng, S.L. T-bet regulates T-independent IgG2a class switching. Int. Immunol. 15, 937–944 (2003).
Wang, X. & Seed, B.A. PCR primer bank for quantitative gene expression analysis. Nucleic Acids Res. 31, e154 (2003).
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.
The authors declare no competing financial interests.
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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