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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 958–964 (2009)Cite this article

A Corrigendum to this article was published on 01 January 2010

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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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Figure 1: Higher 15-HC serum concentrations in human SPMS and secondary progressive EAE.
Figure 2: Inhibition of PARP-1 suppresses axonal loss and progressive disability in secondary progressive EAE.
Figure 3: Activation of PARP-1 during human SPMS and secondary progressive EAE.
Figure 4: Activation of microglia, macrophages and astrocytes by 5-HC via PARP-1.
Figure 5: Signaling events mediating the activation of PARP-1 by 15-HC.
Figure 6: Activation of PARP-1 by 15-HC is mediated by TLR2.

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  • 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.).

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Author notes

  1. Mauricio F Farez and Francisco J Quintana: These authors contributed equally to this work.

Authors and 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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  1. Mauricio F Farez
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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.

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Correspondence to Francisco J Quintana or Howard L Weiner.

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Farez, M., Quintana, F., Gandhi, R. et al. Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE. Nat Immunol 10, 958–964 (2009). https://doi.org/10.1038/ni.1775

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