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Toll-like receptors expression and signaling in glia cells in neuro-amyloidogenic diseases: towards future therapeutic application.

Trudler D, Farfara D, Frenkel D - Mediators Inflamm. (2010)

Bottom Line: TLR signaling was reported to be associated with a yin-yang effect in the CNS.While TLR signaling was linked to neurogenesis, it was also found to be involved in the pathogenesis of neurodegenerative diseases.Understanding the pattern of TLR signaling in the glial cells may lead to the identification of new targets for therapeutic application.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Sherman building, Room 424, Tel Aviv 69978, Israel.

ABSTRACT
Toll-like receptors (TLRs) are known to be expressed by innate immune response cells and to play a critical role in their activation against foreign pathogens. It was recently suggested that TLRs have an important role in the crosstalk between neurons and glial cells in the central nervous system (CNS). TLR signaling was reported to be associated with a yin-yang effect in the CNS. While TLR signaling was linked to neurogenesis, it was also found to be involved in the pathogenesis of neurodegenerative diseases. This paper will focus on TLR signaling in glial cells in neurodegenerative diseases such as Alzheimer's disease, prion diseases, amyotrophic lateral sclerosis, and Parkinson's disease. Understanding the pattern of TLR signaling in the glial cells may lead to the identification of new targets for therapeutic application.

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Related in: MedlinePlus

Microglia TLR signaling in neurodegenerative diseases. Abnormal amyloid deposition in different neurodegenerative diseases may activate microglial cells through TLRs. Microglial activation may lead to further neuronal damage through secretion of proinflammatory cytokines (green), such as IL-6 and TNF-α, or to neuroprotection by secretion of anti-inflammatory cytokines (blue), such as IL-10, which may prevent further neuronal death. Furthermore, recent reports suggest the role of TLRs 2, 4, and 9 signaling in modulating the phagocytosis (red) and clearance of the neurotoxic amyloid deposition.
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fig1: Microglia TLR signaling in neurodegenerative diseases. Abnormal amyloid deposition in different neurodegenerative diseases may activate microglial cells through TLRs. Microglial activation may lead to further neuronal damage through secretion of proinflammatory cytokines (green), such as IL-6 and TNF-α, or to neuroprotection by secretion of anti-inflammatory cytokines (blue), such as IL-10, which may prevent further neuronal death. Furthermore, recent reports suggest the role of TLRs 2, 4, and 9 signaling in modulating the phagocytosis (red) and clearance of the neurotoxic amyloid deposition.

Mentions: Microglial TLRs are crucial as a first line of defence against bacterial or viral infection. In response to the appearance of multiple bacterial or viral TLR agonists, TLR-mediated signaling promotes the production of a variety of inflammatory mediators (reviewed by [33, 34]). In addition, phagocytosis is stimulated by TLR activation, which may be particularly relevant to the clearance of bacteria as well as aggregated or abnormal proteins such as amyloid fibers from the CNS [35, 36] (Figure 1). Like other macrophage-like cells, microglia can express essentially all different TLR family members. While TLR expression is hardly detectable in resting microglia in a healthy CNS, multiple TLRs rapidly appear upon activation of the cells. Primary microglia in vitro constitutively express a wide array of TLRs (TLRs 1–9) at varying levels [26, 37]. Constitutive expression of TLRs is primarily in microglia and largely restricted to the circumventricular organs (CVOs) and meninges, areas with direct access to the circulation, although they may be expressed at lower levels in other regions, too [28, 38, 39]. This unique localization allows the CNS to recognize pathogens which are present in the periphery as well as those that invade the CNS. Like in macrophage, TLRs are exclusively found within endosomal vesicles of microglia, illustrating their primary role in examining the phagocytosed debris. While microglia express all TLRs at readily detectable levels [26], TLRs 1–4 are the most dominant, with TLR2 being the most highly expressed TLR compared to other family members; this applies to microglia in rodents as well as in humans. Lehnard et al. [40] have indicated that microglial cells are the major cell type that expresses TLR4 in the mouse brain.


Toll-like receptors expression and signaling in glia cells in neuro-amyloidogenic diseases: towards future therapeutic application.

Trudler D, Farfara D, Frenkel D - Mediators Inflamm. (2010)

Microglia TLR signaling in neurodegenerative diseases. Abnormal amyloid deposition in different neurodegenerative diseases may activate microglial cells through TLRs. Microglial activation may lead to further neuronal damage through secretion of proinflammatory cytokines (green), such as IL-6 and TNF-α, or to neuroprotection by secretion of anti-inflammatory cytokines (blue), such as IL-10, which may prevent further neuronal death. Furthermore, recent reports suggest the role of TLRs 2, 4, and 9 signaling in modulating the phagocytosis (red) and clearance of the neurotoxic amyloid deposition.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2913815&req=5

fig1: Microglia TLR signaling in neurodegenerative diseases. Abnormal amyloid deposition in different neurodegenerative diseases may activate microglial cells through TLRs. Microglial activation may lead to further neuronal damage through secretion of proinflammatory cytokines (green), such as IL-6 and TNF-α, or to neuroprotection by secretion of anti-inflammatory cytokines (blue), such as IL-10, which may prevent further neuronal death. Furthermore, recent reports suggest the role of TLRs 2, 4, and 9 signaling in modulating the phagocytosis (red) and clearance of the neurotoxic amyloid deposition.
Mentions: Microglial TLRs are crucial as a first line of defence against bacterial or viral infection. In response to the appearance of multiple bacterial or viral TLR agonists, TLR-mediated signaling promotes the production of a variety of inflammatory mediators (reviewed by [33, 34]). In addition, phagocytosis is stimulated by TLR activation, which may be particularly relevant to the clearance of bacteria as well as aggregated or abnormal proteins such as amyloid fibers from the CNS [35, 36] (Figure 1). Like other macrophage-like cells, microglia can express essentially all different TLR family members. While TLR expression is hardly detectable in resting microglia in a healthy CNS, multiple TLRs rapidly appear upon activation of the cells. Primary microglia in vitro constitutively express a wide array of TLRs (TLRs 1–9) at varying levels [26, 37]. Constitutive expression of TLRs is primarily in microglia and largely restricted to the circumventricular organs (CVOs) and meninges, areas with direct access to the circulation, although they may be expressed at lower levels in other regions, too [28, 38, 39]. This unique localization allows the CNS to recognize pathogens which are present in the periphery as well as those that invade the CNS. Like in macrophage, TLRs are exclusively found within endosomal vesicles of microglia, illustrating their primary role in examining the phagocytosed debris. While microglia express all TLRs at readily detectable levels [26], TLRs 1–4 are the most dominant, with TLR2 being the most highly expressed TLR compared to other family members; this applies to microglia in rodents as well as in humans. Lehnard et al. [40] have indicated that microglial cells are the major cell type that expresses TLR4 in the mouse brain.

Bottom Line: TLR signaling was reported to be associated with a yin-yang effect in the CNS.While TLR signaling was linked to neurogenesis, it was also found to be involved in the pathogenesis of neurodegenerative diseases.Understanding the pattern of TLR signaling in the glial cells may lead to the identification of new targets for therapeutic application.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Sherman building, Room 424, Tel Aviv 69978, Israel.

ABSTRACT
Toll-like receptors (TLRs) are known to be expressed by innate immune response cells and to play a critical role in their activation against foreign pathogens. It was recently suggested that TLRs have an important role in the crosstalk between neurons and glial cells in the central nervous system (CNS). TLR signaling was reported to be associated with a yin-yang effect in the CNS. While TLR signaling was linked to neurogenesis, it was also found to be involved in the pathogenesis of neurodegenerative diseases. This paper will focus on TLR signaling in glial cells in neurodegenerative diseases such as Alzheimer's disease, prion diseases, amyotrophic lateral sclerosis, and Parkinson's disease. Understanding the pattern of TLR signaling in the glial cells may lead to the identification of new targets for therapeutic application.

Show MeSH
Related in: MedlinePlus