Invited MinireviewGlial toll-like receptor signaling in central nervous system infection and autoimmunity
Introduction
Toll-like receptors (TLRs) are a large family of evolutionarily conserved pattern recognition receptors in the vertebrate immune system. At least 13 TLR genes exist in mammals, and functional ligands have been identified for 10 [for review see Uematsu and Akira, 2006]. TLRs recognize conserved pathogen-associated molecular patterns (PAMPs) from diverse organisms, including bacteria, viruses, yeast, fungi and parasites. Many well-known PAMPs signal through TLRs, including lipopolysaccharide (LPS; TLR4), double stranded RNA (dsRNA; TLR3), peptidoglycans (PGN; TLR2 with TLR1/6), and CpG DNA (TLR9) (Fig. 1A). All known TLRs with the exception of TLR3 signal through the adaptor protein MyD88 and lead to the activation of the transcription factor nuclear factor κB (NF-κB). TLR3 and TLR4 signal through an MyD88-independent pathway dependent on the adaptor TRIF and activate both NF-κB and Interferon response factor 3 (IRF3).
The limited immune surveillance of the central nervous system (CNS) makes it crucial that resident cells be able to rapidly recognize and respond to infection. Innate immunity in the CNS depends primarily on the functions of glial cells, astrocytes and microglia, which are important for the early control of pathogen replication and direct the recruitment and activation of cells of the adaptive immune system required for pathogen clearance (Bailey et al., 2006). In this review, we will focus on the activation of TLRs expressed on glial cells and the functional outcomes for the CNS. We will discuss the role of TLRs in innate immune responses of glia in vitro as well as their roles during CNS infection in vivo. The ability to mount an effective innate immune response in the CNS is likely critical to eliminate pathogens and often vital to host survival. However, it is also evident that chronic or dysregulated inflammation in the CNS can cause tissue damage and neurodegeneration and the role of TLRs in this process will be discussed. Finally, we will discuss how TLRs might be involved during the development of CNS autoimmunity.
Section snippets
Expression of TLRs in CNS Glial Cells
Microglia are CNS tissue resident macrophages and act as immune sentinels of the brain. In accordance with this view, primary microglia in vitro constitutively express a wide complement of TLRs (TLRs1–9) at varying levels (Bsibsi et al., 2002, Olson and Miller, 2004). In comparison, primary astrocytes also express a wide variety of TLRs, but at lower levels. Murine astrocytes express TLRs1–9, with particularly high levels of TLR3 (Carpentier et al., 2005, McKimmie and Fazakerley, 2005),
TLRs in the induction of innate immune functions of glia in Vitro
It is well known that both astrocytes and microglia have the potential to contribute to innate immunity in the CNS following exposure to pathogens or PAMPs (Fig. 1B). The immune signals to which glia are able to respond and their functions during both innate and adaptive immune responses have been reviewed extensively elsewhere (Bailey et al., 2006), and we will only summarize them briefly here. Innate immune functions of astrocytes and microglia include anti-microbial properties via the
Function of TLRs during CNS infection in vivo
The use of mice genetically deficient for various TLRs has allowed the study of their in vivo role during CNS infection, although potential unique contributions of TLR signaling on glia in the CNS have not yet been thoroughly assessed. Recently, two groups have used a bone marrow (BM) transplant system to assess the role of TLR4 on peripheral and CNS-resident cells in an LPS-induced injury model (Chakravarty and Herkenham, 2005, Zhou et al., 2006). In these studies, wildtype (WT) or
Neurotoxicity caused by TLR stimulation
Although the stimulation of TLRs on glial cells activate functions that are important for the elimination of pathogens (Fig. 1C), these same functions can be toxic to cells of the CNS that have limited regenerative capacity (Fig. 1D). Microglia stimulated with LPS in vitro are toxic to neurons and oligodendrocytes in a TLR4-dependent manner (Lehnardt et al., 2002, Lehnardt et al., 2003). Similarly, microglia exposed to GBS or S. pneumoniae serotype 2 also display neurotoxic properties,
Functions of TLRs in autoimmunity
Multiple sclerosis (MS) is a CD4+ T cell-mediated autoimmune demyelinating disease of the CNS (Sospedra and Martin, 2005). Although its exact etiology is unknown, epidemiologic evidence suggests a viral trigger (Sospedra and Martin, 2005). The principal murine model of MS is experimental autoimmune encephalomyelitis (EAE), in which an autoimmune response is primed in the periphery by the administration of myelin peptides or proteins emulsified in complete Freund’s adjuvant (CFA), or by adoptive
Conclusions
Although the CNS is no longer considered to be entirely immune-privileged, there are significant obstacles to mounting immune responses in the CNS; notably the limited immune surveillance and general immunosuppressive properties (Bailey et al., 2006). These properties make it critical that CNS resident cells be able to recognize and efficiently respond to infection, and coordinate an immune response capable of clearing the infection without causing extensive tissue damage. Since the recognition
Acknowledgments
Work in the Miller Lab is supported by Grants from the NIH, the National Multiple Sclerosis Society, and the Myelin Repair Foundation. PAC was supported by NIH Training Grant F31 NS048807. DSD is supported by NIH Training Grant T32 AI060523.
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These authors contributed equally to the preparation of this article.