Regulation of autoimmune encephalomyelitis by toll-like receptors Monica Marta a, ⁎, Ute C. Meier a , Anna Lobell b a Neuroimmunology, Neuroscience Centre, ICMS, Barts and The London School of Medicine and Dentistry, London, UK b Department of Medical Sciences, Uppsala University, Uppsala, Sweden article info abstract Article history: Received 24 December 2008 Accepted 12 January 2009 Available online 27 January 2009 Experimental autoimmune encephalomyelitis (EAE) is a Th17-mediated autoimmune disease and an animal model for multiple sclerosis (MS). Complete Freund's adjuvant (CFA) contains pathogen-associated molecular patterns (PAMPs) that bind toll-like receptors (TLRs), and is necessary to induce EAE. Upstream TLR signals modify innate and adaptive immune responses in EAE. In detail, the common TLR adaptor molecule MyD88 is necessary for induction of EAE, and mediates activation of peripheral myeloid dendritic cells (mDCs) and differentiation of autoimmune Th17 cells. The stimulatory TLRs have not yet been identified for Th17 cells. TLR4 down regulates disease severity in EAE and Th17 cell responses, but promotes Th1 cell responses, which may inhibit the differentiation of Th17 cells. Moreover, treatment with a TLR4 ligand tolerizes mice and prevents EAE. TLR9 down regulates disease severity in myelin oligodendrocyte glycoprotein (MOG)-induced EAE, whereas it promotes disease in MOG 35–55 - induced EAE. Thus MyD88, TLR4 and TLR9 modify the disease process in EAE. Both endogenous and CFA-derived TLR ligands are implicated to modulate the disease process. © 2009 Elsevier B.V. All rights reserved. Contents 1. Multiple sclerosis and experimental autoimmune encephalomyelitis . . . . . . . . . . . . . . . . . . . . . . . . . . . 506 2. Toll-like receptors and innate immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 3. Regulation of encephalitogenic CD4 T cell responses and EAE by TLRs . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 3.1. EAE is mediated by MyD88 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 3.2. Mice deficient in TLR6 or TLR2 are susceptible to EAE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 3.3. Modulation of EAE by TLR4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 3.4. Modulation of EAE by TLR9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508 3.5. TLR function in neuroinflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509 . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509 1. Multiple sclerosis and experimental autoimmune encephalomyelitis Multiple sclerosis (MS) is a chronic inflammatory, demye- linating and neurodegenerative disorder of the central nervous system (CNS). It affects young adults with an increasing female predominance and constitutes the most important cause of non-traumatic neurological disability. It is Autoimmunity Reviews 8 (2009) 506–509 ⁎ Corresponding author. Neuroimmunology Unit — Neurosciences, Insti- tute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E12AT, UK. Tel.: +44 20 78822677; fax: +44 20 78822180. E-mail address: m.calado-marta@qmul.ac.uk (M. Marta). 1568-9972/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2009.01.006 Contents lists available at ScienceDirect Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev