Elsevier

Brain Research Reviews

Volume 59, Issue 2, March 2009, Pages 278-292
Brain Research Reviews

Review
Toll-like receptors in neurodegeneration

https://doi.org/10.1016/j.brainresrev.2008.09.001Get rights and content

Abstract

The key roles of toll-like receptors (TLRs) as mediators of the detection and responses of immune cells to invading pathogens are well known. There are at least 13 mammalian TLRs which are integral membrane proteins with a leucine-rich extracellular domain and a cytoplasmic domain similar to that of the interleukin-1 receptor which initiates downstream signaling through kinases to activate transcription factors such as AP-1 and NFκB. TLRs are activated in glial cells (microglia, astrocytes and oligodendrocytes) and lymphocytes that infiltrate the nervous system in response to inflammation caused by infectious agents, tissue injury or autoimmune conditions. By inducing the production of pro-inflammatory cytokines and cell adhesion molecules in immune cells, TLRs may indirectly damage neurons in conditions such as ischemic stroke and multiple sclerosis. Recent findings suggest that neurons also express a subset of TLRs and that their activation promotes neuronal degeneration in experimental models of stroke and Alzheimer's disease. TLRs may also play roles in regulating the processes of neurogenesis and neurite outgrowth, suggesting roles in neuronal plasticity. A better understanding of the molecular and cellular biology of TLRs in the normal and diseased nervous system, may lead to novel approaches for preventing neuronal degeneration and promoting recovery of function in an array of neurodegenerative conditions.

Introduction

Toll-like receptors (TLRs) are transmembrane pattern-recognition receptors (PRRs) that initiate signals in response to diverse pathogen-associated molecular patterns (PAMPs) (Kawai and Akira, 2007a). The involvement of Toll receptors in innate immunity was first described in Drosophila in 1988 by Hashimoto et al. (1988). Following the description of Drosophila Toll in host defense against fungal infection, a mammalian homologue was identified (Medzhitov et al., 1997) which recognizes lipopolysaccharides (LPS), a major cell wall component of gram-negative bacteria (Hoshino et al., 1999). Subsequently, a family of proteins structurally related to Drosophila Toll was identified, collectively referred to as TLRs. Depending on their arrangement as either homo- or heterodimers, each TLR complex recognizes distinct PAMPs derived from various microorganisms, including bacteria, viruses, protozoa and fungi (Kawai and Akira, 2007a).

TLRs are expressed in a variety of mammalian immune-related cell types such as B cells (Gerondakis et al., 2007), mast cells (Iwamura and Nakayama, 2008), NK cells (Eriksson et al., 2006), regulatory T cells (Sutmuller et al., 2007), macrophages, monocytes, dendritic cells (Kaisho and Akira, 2006), neutrophils (Sabroe and Whyte, 2007), basophils (Yoshimoto and Nakanishi, 2006) as well as non-immune cells such as epithelial (Yoshimoto and Nakanishi, 2006) and endothelial cells (Gibson et al., 2008). TLRs are also present in the brain where, until recently, their expression was believed to be limited to microglia (Olson and Miller, 2004), astrocytes (Bowman et al., 2003), and oligodendrocytes (Bsibsi et al., 2002). Recent findings, however, suggest that neurons express at least some TLRs (Tang et al., 2007). While TLRs mediate immunity in Drosophila (Lemaitre et al., 1996), they were initially identified based on their role in establishing embryonic dorso-ventral polarity during body axis development (Belvin and Anderson, 1996). This implies a wider range of functionality than purely innate immunity. Indeed, TLRs have been implicated in several non-immune processes, such as bone metabolism (Bar-Shavit, 2008), neurogenesis (Rolls et al., 2007) and brain development (Ma, 2006, Ma, 2007).

Until recently, TLRs have been examined predominantly for their contribution to immune-related disorders. However, cumulative evidence suggests that TLRs not only contribute to pathophysiology, but also play a vital role in facilitating neurodegenerative conditions. This review summarizes our current knowledge of the role of TLRs in the pathogenesis of brain disorders such as ischemic stroke, Alzheimer’s disease and multiple sclerosis, as well as the therapeutic potential of TLR intervention in such diseases.

Section snippets

Toll-like receptors

TLRs are major PRRs that have a central role in the initiation of innate immunity against invading microbial pathogens. These single membrane spanning proteins bear a leucine-rich extracellular domain, through which they recognize PAMP, and a cytoplasmic Toll/IL-1 Receptor (TIR) domain similar to that of the interleukin-1 receptor (IL-1R), which initiates downstream signaling (Kawai and Akira, 2007a). Each TLR by itself or in combination with other TLRs recognize distinct PAMPs that include

Toll-like receptor signaling

Functional TLR signal transduction is complex and relies on receptor dimerization as well as the presence of accessory proteins and co-receptors, which regulate the signaling pathways initiated by each receptor. After recognition of PAMPs, TLRs activate the signaling components which results in appropriate immune responses required for host defense. The cytoplasmic region of TLRs shares a stretch of Toll/IL-1 receptor (TIR) domain, which mediates homo- and heterophilic interactions between TLRs

Toll-like receptors in the nervous system

TLRs have traditionally been considered receptors expressed solely on antigen presenting cells of the immune system such as B cells, dendritic cells, monocytes and macrophages, where they mediate innate immunity. It is increasingly clear, however, that nearly all cells within the body express TLRs, including those within the CNS. This section will focus on the role of TLRs in different brain cell types such as microglial cells, astrocytes, oligodendrocytes and neurons.

Toll-like receptors in neurodegeneration

Although TLRs are traditionally considered to respond to invading pathogens, they can be activated in the absence of microbial infection (Zhang and Schluesener, 2006) and regulate neurogenesis (Rolls et al., 2007). Studies examining inflammatory markers in normal brain aging have also suggested a dynamic regulation of TLRs with advancing age. Aging is associated with increased secretion of pro-inflammatory cytokines, whereas levels of the anti-inflammatory cytokines decrease (Godbout and

Therapeutic approaches

Evidence is emerging that TLRs are not only activated in response to microbial infection, but are critically involved in mediating neurological dysfunction. The extensive involvement of TLRs in neurodegenerative disorders provides ample opportunity for promoting and/or inhibiting their signaling to intervene in disease progression. However, it may prove exceedingly difficult to achieve the correct balance and appropriate timing of such interventions. Proper targeting of TLRs will require

Conclusion

It has become evident in recent years that TLR expression and functionality extends well beyond the boundaries of immune cells, as increasing numbers of cells appear to express and respond to TLRs and their ligands. Among the most interesting non-immune tissues that appear to express TLRs are cells within the CNS. All types of CNS residing cells, namely astrocytes, microglia, oligodendrocytes and neurons, express different subsets of TLRs in both murine models and human cells. It is not

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