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Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells

Nature Immunology volume 8, pages 74–83 (2007)Cite this article

Abstract

Relapses and disease exacerbations are vexing features of multiple sclerosis. Osteopontin (Opn), which is expressed in multiple sclerosis lesions, is increased in patients’ plasma during relapses. Here, in models of multiple sclerosis including relapsing, progressive and multifocal experimental autoimmune encephalomyelitis (EAE), Opn triggered recurrent relapses, promoted worsening paralysis and induced neurological deficits, including optic neuritis. Increased inflammation followed Opn administration, whereas its absence resulted in more cell death of brain-infiltrating lymphocytes. Opn promoted the survival of activated T cells by inhibiting the transcription factor Foxo3a, by activating the transcription factor NF-κB through induction of phosphorylation of the kinase IKKβ and by altering expression of the proapoptotic proteins Bim, Bak and Bax. Those mechanisms collectively suppressed the death of myelin-reactive T cells, linking Opn to the relapses and insidious progression characterizing multiple sclerosis.

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Figure 1: Opn induces worsening autoimmune relapses and severe progression of autoimmune demyelinating disease.
Figure 2: Opn inhibits cell death but does not affect cell division.
Figure 3: Opn regulates the activation of Foxo3a and NF-κB and expression of Bim, Bak and Bax.
Figure 4: Mode of cell death inhibited by Opn in T cell.
Figure 5: Opn promotes the survival of adoptively transferred T cells in vivo.

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Acknowledgements

We thank G.R. Crabtree, P.P. Jones, P.J. Utz, T.W. Mak (University of Toronto) and D.R. Green (St. Jude Children's Research Hospital) for discussions; J.H. Kim, M.J. Eaton and C.K. Chung for technical assistance; C.J. Shabrami and M.M. Winslow for critical review of the manuscript; S. Rittling and D.T. Denhardt (Rutgers University) for Opn-knockout mice; and V. Kuchroo (Harvard University) for 2D2 mice. Supported by the National Health Institutes, the National Multiple Sclerosis Society, the Phil N. Allen Trust, a Stanford Graduate Fellowship (E.M.H.), a Korean Government Overseas Scholarship (E.M.H.) and a National Multiple Sclerosis Society Career Transitional Award (S.Y.).

Author information

Authors and Affiliations

  1. Interdepartmental Program in Immunology, Stanford University School of Medicine, Stanford, 94305, California, USA

    Eun Mi Hur & Lawrence Steinman

  2. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, 94305, California, USA

    Eun Mi Hur, Sawsan Youssef, M Edward Haws, Susan Y Zhang & Lawrence Steinman

  3. Department of Pathology (Neuropathology), Stanford University School of Medicine, Stanford, 94305, California, USA

    Raymond A Sobel

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Contributions

E.M.H. and S.Y. designed and did the experiments and prepared the manuscript; M.E.H. assisted with cell fractionation; S.Y.Z. assisted in assigning scores to mice with EAE; R.A.S. contributed to histology; and L.S. supervised all studies and preparation of the manuscript.

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Correspondence to Lawrence Steinman.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Autoimmune optic neuritis induced by OPN in MOG-specific TCR transgenic mice with EAE. (PDF 2949 kb)

Supplementary Fig. 2

Residual LPS in purified OPN does not affect clinical score of EAE. (PDF 410 kb)

Supplementary Fig. 3

Increased T cell proliferation by OPN. (PDF 234 kb)

Supplementary Fig. 4

The time course expression of Bim, Bak and Bax after T cell activation in vitro. (PDF 1562 kb)

Supplementary Fig. 5

OPN does not affect Fas-induced cell death. (PDF 252 kb)

Supplementary Fig. 6

OPN inhibits nuclear translocation of AIF. (PDF 1623 kb)

Supplementary Fig. 7

Schematic diagram of OPN-induced survival of T cell. (PDF 581 kb)

Supplementary Fig. 8

Schematic diagram of the suggested model for autoimmune relapse. (PDF 778 kb)

Supplementary Table 1

EAE induced in OPN-KO and OPN-WT mice. (PDF 59 kb)

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Hur, E., Youssef, S., Haws, M. et al. Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells. Nat Immunol 8, 74–83 (2007). https://doi.org/10.1038/ni1415

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