ReviewToll-like receptors in neurodegeneration
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
References (127)
Pathogen recognition and innate immunity
Cell
(2006)Inflammation and Alzheimer's disease
Neurobiol. Aging
(2000)Reduced cerebral ischemia–reperfusion injury in Toll-like receptor 4 deficient mice
Biochem. Biophys. Res. Commun.
(2007)Cytoplasmic translocation of Olig2 in adult glial progenitors marks the generation of reactive astrocytes following autoimmune inflammation
Exp. Neurol.
(2006)Activation of Toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide
J. Biol. Chem.
(2006)Intrahippocampal LPS injections reduce Abeta load in APP+PS1 transgenic mice
Neurobiol. Aging
(2001)Preferential expression and function of Toll-like receptor 3 in human astrocytes
J. Neuroimmunol.
(2005)- et al.
Interleukin-6 in the aging brain
J. Neuroimmunol.
(2004) The Toll gene of Drosophila, required for dorsal–ventral embryonic polarity, appears to encode a transmembrane protein
Cell
(1988)Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion
J. Neuroimmunol.
(2007)
Toll-like receptor function and signaling
J. Allergy Clin. Immunol.
Signaling to NF-kappaB by Toll-like receptors
Trends Mol. Med.
TLR signaling
Semin. Immunol.
TLR-4 deficiency protects against focal cerebral ischemia and axotomy-induced neurodegeneration
Neurobiol. Dis.
Impact of the Asp299Gly polymorphism in the toll-like receptor 4 (tlr-4) gene on disease course of multiple sclerosis
J. Neuroimmunol.
Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia
J. Neuroimmunol.
The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults
Cell
Innate immune receptor expression in normal brain aging
Neuroscience
Role of microglia in senile plaque formation
Neurobiol. Aging
Effect of the functional toll-like receptor 4 Asp299Gly polymorphism on susceptibility to late-onset Alzheimer's disease
Neurosci. Lett.
Expression and distribution of Toll-like receptors in the brain during murine neurocysticercosis
J. Neuroimmunol.
Disturbance of oligodendrocyte development, hypomyelination and white matter injury in the neonatal rat brain after intracerebral injection of lipopolysaccharide
Brain Res. Dev. Brain Res.
p38 MAPK activation controls the TLR3-mediated up-regulation of cytotoxicity and cytokine production in human NK cells
Blood
Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3
Nature
Toll-like receptors are key participants in innate immune responses
Biol. Res.
Toll-like receptors in defense and damage of the central nervous system
J. Neuroimmune. Pharmacol.
Inhibition of toll-like receptor signaling in primary murine microglia
J. Neuroimmune Pharmacol.
TLR4 mutations are associated with endotoxin hyporesponsiveness in humans
Nat. Genet.
MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists
J. Immunol.
Role of Toll-like receptor 4 in acute myocardial infarction and longevity
Jama
Taking a toll on the bones: regulation of bone metabolism by innate immune regulators
Autoimmunity
Regulation of CD14 expression on human adult central nervous system-derived microglia
J. Neurosci. Res.
A conserved signaling pathway: the Drosophila toll-dorsal pathway
Annu. Rev. Cell Dev. Biol.
Cultured astrocytes express toll-like receptors for bacterial products
Glia
Toll-like receptor interactions: tolerance of MyD88-dependent cytokines but enhancement of MyD88-independent interferon-beta production
Immunology
Broad expression of Toll-like receptors in the human central nervous system
J. Neuropathol. Exp. Neurol.
Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators
Glia
Identification of soluble CD14 as an endogenous agonist for Toll-like receptor 2 on human astrocytes by genome-scale functional screening of glial cell derived proteins
Glia
Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals
J. Neurosci.
Differential activation of astrocytes by innate and adaptive immune stimuli
Glia
Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke
Circulation
Phagocytosis of apoptotic inflammatory cells by microglia and its therapeutic implications: termination of CNS autoimmune inflammation and modulation by interferon-beta
Glia
TGF-beta 2 reduces demyelination, virus antigen expression, and macrophage recruitment in a viral model of multiple sclerosis
J. Immunol.
TLRs mediate IFN-gamma production by human uterine NK cells in endometrium
J. Immunol.
Beta-amyloid peptide potentiates inflammatory responses induced by lipopolysaccharide, interferon-gamma and 'advanced glycation endproducts' in a murine microglia cell line
Eur. J. Neurosci.
Regulating B-cell activation and survival in response to TLR signals
Immunol. Cell Biol.
Engagement of specific innate immune signaling pathways during Porphyromonas gingivalis induced chronic inflammation and atherosclerosis
Front Biosci.
Virus-mediated autoimmunity in Multiple Sclerosis
J. Autoimmune Dis.
Microglial activation is required for Abeta clearance after intracranial injection of lipopolysaccharide in APP transgenic mice
J. Neuroimmune Pharmacol.
Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product
J. Immunol.
Cited by (369)
TransNeT-CGP: A cluster-based comorbid gene prioritization by integrating transcriptomics and network-topological features
2024, Computational Biology and ChemistryOndansetron attenuates cisplatin-induced behavioral and cognitive impairment through downregulation of NOD-like receptor inflammasome pathway
2024, Toxicology and Applied PharmacologyEmerging evidence for endogenous neurosteroid modulation of pro-inflammatory and anti-inflammatory pathways that impact neuropsychiatric disease
2024, Neuroscience and Biobehavioral ReviewsDual role of nitric oxide in Alzheimer's disease
2023, Nitric Oxide - Biology and Chemistry
- 1
Authors contributed equally to this review.