Regulation of Toll-Like Receptor (TLR) Signaling Pathway by Polyphenols in the Treatment of Age-Linked Neurodegenerative Diseases: Focus on TLR4 Signaling

Abstract

Neuronal dysfunction initiates several intracellular signaling cascades to release different proinflammatory cytokines and chemokines, as well as various reactive oxygen species. In addition to neurons, microglia, and astrocytes are also affected by this signaling cascade. This release can either be helpful, neutral or detrimental for cell survival. Toll-like receptors (TLRs) activate and signal their downstream pathway to activate NF-κB and pro-IL-1β, both of which are responsible for neuroinflammation and linked to the pathogenesis of different age-related neurological conditions. However, herein, recent aspects of polyphenols in the treatment of neurodegenerative diseases are assessed, with a focus on TLR regulation by polyphenols. Different polyphenol classes, including flavonoids, phenolic acids, phenolic alcohols, stilbenes, and lignans can potentially target TLR signaling in a distinct pathway. Further, some polyphenols can suppress overexpression of inflammatory mediators through TLR4/NF-κB/STAT signaling intervention, while others can reduce neuronal apoptosis via modulating the TLR4/MyD88/NF-κB-pathway in microglia/macrophages. Indeed, neurodegeneration etiology is complex and yet to be completely understood, it may be that targeting TLRs could reveal a number of molecular and pharmacological aspects related to neurodegenerative diseases. Thus, activating TLR signaling modulation via natural resources could provide new therapeutic potentiality in the treatment of neurodegeneration.

Keywords: MyD88; NF-κB; Toll-like receptor; inflammasome; neurodegenerative disease; polyphenols.

Figure 1

Cell surface and endosomal signaling pathway of TLRs. TLR4, TLR5, and heterodimers TLR1/2 and TLR2/6 sense bacterial invasion and initiate intracellular TLR-signaling pathway. Following the activation, each of them recruits several adaptors in the cytoplasm and activate MyD88-downstream. That means the activation of IRAK4 and phosphoryl IRAK1 that then bind to TRAF6 (not shown). TRAF6 then recruit MKK4 and IKKα/β pathway, where MKK4 initiate JNK and activate c-FOS and JUN, and push into the nucleus. While IKKα/β activates NFκB and its pro-inflammatory subunits and moves into the nucleus, similarly, endosomal TLRs (TLR3, 7–9) triggers the NFκB and MAPK pathways via involving MyD88 and IRAK4. Additionally, TLR3, MyD88 independently, recruit TRIF-pathway leading to the phosphorylation and dimerization of IRF7. Both, surface and endosomal pathway ultimately result in a production of type I interferon and release of proinflammatory cytokines. MyD88, myeloid Differentiation primary response 88; IRAK4, interleukin-1 receptor-associated kinase-4; TRAF6, TNF receptor-associated factor-6; MKK4, mitogen-activated protein kinase kinase-4; IKKα/β, IκK kinase; JNK, c-Jun N-terminal kinase; TIRF, TIR-domain-containing adapter-inducing interferon-β; IRF3/7, interferon regulatory factor-3/7.

Figure 2

TLRs-signaling in microglial cells in different neurodegenerative disease progression. 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 (red), such as IL-6 and TNF-α, or neuroprotection by secretion of anti-inflammatory cytokines (green), such as IL-10, which may prevent further neuronal death. Furthermore, recent reports suggest TLRs 2, 4, and 9 signaling may modulate the phagocytosis (blue) and clear the neurotoxic amyloid deposition (108). Aβ stimulation, mononuclear cells of normal subjects up-regulate the transcription of β-1,4-mannosyl-glycoprotein 4-β-Nacetylglucosaminyltransferase (MGAT3).

Figure 3

Polyphenols modulating upstream (TLR activation) and downstream (different kinase and transcription factors) pathway of surface and endogenous TLR to reduce or demolish pro-inflammatory cytokines and type I interferon generation.