Role of Toll-like receptor/MYD88 signaling in neurodegenerative diseases

Wang, Xiang; Chao, Zhang-Yong; Feng, Du-Yi

doi:10.1515/revneuro-2014-0067

Cited by 49 publications

(30 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Indeed, we also found that TLR2 and TLR4 were expressed on RBA-1 cells. A previous study has shown that TLR-mediated signalings play a critical role in neurodegenerative diseases, such as Alzheimer s disease, Parkinson s disease, amyotrophic lateral sclerosis, and multiple system atrophy [37]. Here, we proved that LPS potentially enhanced MMP-9 expression and cell migration, mainly via TLR4 activation, as transfection with TLR4 but not TLR2 siRNA attenuated the LPS-mediated responses and phosphorylation of downstream signaling molecules.…”

Section: Discussionsupporting

confidence: 53%

Lipopolysaccharide-Induced Matrix Metalloproteinase-9 Expression Associated with Cell Migration in Rat Brain Astrocytes

Yang

Lin

Hsiao

et al. 2019

IJMS

View full text Add to dashboard Cite

Neuroinflammation is a landmark of neuroinflammatory and neurodegenerative diseases. Matrix metalloproteinase (MMP)-9, one member of MMPs, has been shown to contribute to the pathology of these brain diseases. Several experimental models have demonstrated that lipopolysaccharide (LPS) exerts a pathological role through Toll-like receptors (TLRs) in neuroinflammation and neurodegeneration. However, the mechanisms underlying LPS-induced MMP-9 expression in rat brain astrocytes (RBA-1) are not completely understood. Here, we applied pharmacological inhibitors and siRNA transfection to assess the levels of MMP-9 protein, mRNA, and promoter activity, as well as protein kinase phosphorylation in RBA-1 cells triggered by LPS. We found that LPS-induced expression of pro-form MMP-9 and cell migration were mediated through TLR4, proto-oncogene tyrosine-protein kinase (c-Src), proline-rich tyrosine kinase 2 (Pyk2), platelet-derived growth factor receptor (PDGFR), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), p38 mitogen-activated protein kinase (MAPK), and Jun amino-terminal kinase (JNK)1/2 signaling molecules in RBA-1 cells. In addition, LPS-stimulated binding of c-Jun to the MMP-9 promoter was confirmed by chromatin immunoprecipitation (ChIP) assay, which was blocked by pretreatment with c-Src inhibitor II, PF431396, AG1296, LY294002, Akt inhibitor VIII, p38 MAP kinase inhibitor VIII, SP600125, and tanshinone IIA. These results suggest that in RBA-1 cells, LPS activates a TLR4/c-Src/Pyk2/PDGFR/PI3K/Akt/p38 MAPK and JNK1/2 pathway, which in turn triggers activator protein 1 (AP-1) activation and ultimately induces MMP-9 expression and cell migration.

show abstract

Section: Discussionsupporting

confidence: 53%

Lipopolysaccharide-Induced Matrix Metalloproteinase-9 Expression Associated with Cell Migration in Rat Brain Astrocytes

Yang

Lin

Hsiao

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

“…When TLRs recognize PAMPs or DAMPs, the DD of MyD88 interacts with the DD of IL-1 receptor-associated kinase-4 (IRAK-4) and forms the MyD88-IRAK-4 complex, which recruits IRAK-1 and IRAK-2, resulting in the phosphorylation of IRAKs. IRAKs leave MyD88 after phosphorylation and interact with tumor necrosis factor receptor-associated factor 6 (TRAF6; Xiang et al, 2015). TRAF6 then induces the activation of TGFβ activated kinase-1 (TAK-1) and TAK1-binding proteins (TAB) 2 and 3, which consequently activate the nuclear factor-κB (NF-κB) signaling pathway by phosphorylating I-κB (IκB).…”

Section: Structures and Biological Functions Of Tlrs And Myd88mentioning

confidence: 99%

“…Additionally, TAK-1 can also activate c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase (MAPK) and Phosphatidylinositol 3-Kinases (PI3K). The activation of these downstream kinases and pathways leads to a cascade of inflammatory responses (Xiang et al, 2015).…”

Section: Structures and Biological Functions Of Tlrs And Myd88mentioning

confidence: 99%

Inflammatory Role of TLR-MyD88 Signaling in Multiple Sclerosis

Chen

Chu

et al. 2020

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Multiple sclerosis (MS) is a neuro-autoimmune and neurodegenerative disorder leading to chronic inflammation, demyelination, axonal, and neuronal loss in the central nervous system (CNS). Despite intense research efforts, the pathogenesis of MS still remains unclear. Toll-like receptors (TLRs) are a family of type I transmembrane receptors that play a crucial role in the innate immune response. Myeloid differentiation factor 88 (MyD88) is the adaptor of major TLRs. It has been widely considered that the TLR-MyD88 signaling pathway plays an important role in the occurrence and development of autoimmune disease. Data have revealed that the TLR-MyD88 signaling may be involved in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE), an animal model for MS, by regulating the antigen presentation of dendritic cells, the integrity of blood-brain barrier (BBB), and the activation of T cells and B cells. Here, we summarize the role of TLRs and MyD88 in MS and discuss the possible therapies that are based on these molecules.

show abstract

“…In particular, TRL4, a member of the TRLs family that has been involved in neuroinflammatory diseases [41], is expressed on microglia and it is activated in response to different stimuli/injury. The TRL4 stimulation triggers the activation of signaling cascades which generally culminate in the expression of the Nuclear Factor-kappa B (NF-κB) [42] and the NF-κB-mediated transcription of pro-inflammatory genes [43,44,45]. The prolonged release of proinflammatory mediators such as cytokines (IL-1β, IL-6, TNF-α, IL-8, TGF-β), chemokines, prostaglandins, inducible nitric oxide synthase, cyclooxygenase-2 and free radicals by microglia, leads to chronic inflammation and stimulates the adaptive immune response, mediated by peripheral T-cells and macrophages that are recruited in the CNS.…”

Section: The Wnt Canonical Signaling In Neuroinflammationmentioning

confidence: 99%