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Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE

Nature Immunology volume 10, pages 958964 (2009) | Download Citation

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  • A Corrigendum to this article was published on 01 January 2010

This article has been updated

Abstract

Multiple sclerosis is an inflammatory disease of the central nervous system that begins as a relapsing-remitting disease (RRMS) and is followed by a progressive phase (SPMS). The progressive phase causes the greatest disability and has no effective therapy, but the processes that drive SPMS are mostly unknown. Here we found higher serum concentrations of 15α-hydroxicholestene (15-HC) in patients with SPMS and in mice with secondary progressive experimental autoimmune encephalomyelitis (EAE) but not in patients with RRMS. In mice, 15-HC activated microglia, macrophages and astrocytes through a pathway involving Toll-like receptor 2 (TLR2) and poly(ADP-ribose) polymerase 1 (PARP-1). PARP-1 activity was higher in monocytes of patients with SPMS, and PARP-1 inhibition suppressed the progression of EAE. Thus, the TLR2–PARP-1 pathway is a potential new therapeutic target in SPMS.

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Change history

  • 18 September 2009

    NOTE: In the version of this article initially published, two citations were not included. These citations, together with text describing their content, have been added to page 958, column 2, as follows: “As neuronal loss is thought to contribute to the pathogenesis of progressive multiple sclerosis5, and as PARP-1 inhibitors suppress the incidence and severity of experimental autoimmune encephalomyelitis (EAE)36,37, we investigated the function of 15-oxysterols in multiple sclerosis and EAE.” The added references are as follows:   36. Scott, G.S. et al. Role of poly(ADP-ribose) synthetase activation in the development of experimental allergic encephalomyelitis. J. Neuroimmunol. 117, 78–86 (2001).  37. Scott, G.S. et al. The therapeutic effects of PJ34 [N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide.HCl], a selective inhibitor of poly(ADP-ribose) polymerase, in experimental allergic encephalomyelitis are associated with immunomodulation. J. Pharmacol. Exp. Ther. 310, 1053–1061 (2004).   The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank A.S. Basso (Universidade Federal de São Paulo) for discussions, and M. Oukka (Harvard Medical School) for TLR2-deficient mice. Supported by the US National Institutes of Health (AI435801 and NS38037), the US National Multiple Sclerosis Society (PP1289 to H.L.W.) and the Human Frontiers of Science Program Organization (F.J.Q.).

Author information

Author notes

    • Mauricio F Farez
    •  & Francisco J Quintana

    These authors contributed equally to this work.

Affiliations

  1. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Mauricio F Farez
    • , Francisco J Quintana
    • , Roopali Gandhi
    •  & Howard L Weiner
  2. Molecular Biology Service, University of Sevilla, Sevilla, Spain.

    • Guillermo Izquierdo
    •  & Miguel Lucas
  3. Multiple Sclerosis Unit, University of Sevilla, Sevilla, Spain.

    • Guillermo Izquierdo

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Contributions

M.F.F and F.J.Q. did experiments and analyzed data; R.G. provided purified human monocytes; G.I and M.L. contributed samples; and M.F.F., F.J.Q. and H.L.W. wrote the manuscript.

Corresponding authors

Correspondence to Francisco J Quintana or Howard L Weiner.

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DOI

https://doi.org/10.1038/ni.1775

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