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Table 1 Evidence of the involvement of TLRs in PD through different studies

From: The role of Toll-like receptors and neuroinflammation in Parkinson’s disease

Study design Type of evidence Year Most pronounced result Conclusion References
Comparing two genetic variants of TLR2 in the Han Chinese population Clinical 2017 The variant allele T of the rs3804099 was higher in sporadic PD cases than rs3804100 allele Single nucleotide polymorphism of TLR2 is associated with the development of sporadic PD in the Han Chinese population [83]
Comparing the blood cells of PD patients and control group in response to TLR3 or TLR7,8 agonists Clinical 2016 Patient blood cells produced lower cytokine levels after administration of TLR2 and TLR7/8 compared to the control group Blood leukocyte TLR2 and TLR7/8 are impaired in PD, whose association with PD brain damages should be investigated in future studies [149]
Using flow cytometry and western blot to find TLR2 and TLR4 expression in blood and brain of PD patients Clinical 2014 Increased expression of TLR2 and TLR4 in circulating monocytes, and increased TLR4 in B cells and caudate and putamen brain regions in PD patients TLR2 and TLR4 are modulated in the blood and brain of PD patients [150]
Examining the expression of TLR2 in postmortem brain tissue from PD patients and matched controls Clinical 2017 TLR2 is increased in PD brain its level correlates with the α-synuclein accumulation, the neuronal TLR2 expression (but not glial expression) was associated with PD staging The increased expression of TLR2 on neurons might serve as a target for PD therapy [151]
Comparing the phenotype and TLR2 expression between PD patients and incidental Lewy body disease (iLBD) cases and control group Clinical 2014 Pronounced increase of microglial TLR2 expression in iLBD cases (but not PD cases) compared to control,
Increase in amoeboid microglia in PD cases
TLR2 may play a significant role in microglia-mediated responses in PD [152]
In vitro study, comparing the response of murine TLR4-knockdown microglia and wild-type microglia to Paraquat Clinical 2020 Paraquat-induced production of inflammatory cytokines was significantly reduced in TLR4-knockdown microglia TLR4 contributes to neuroinflammation in the Paraquat-induced model of neurodegeneration [153]
Comparing postmortem brains of PD dementia (PDD) and PD with no dementia (PDND) patients and control group Clinical 2020 Upregulation of TLR4 in the substantia nigra, frontal cortex, and amygdala in both PDD and PDND patients compared to control group TLR4 contributes to neuroinflammation in PD [97]
Comparing the colonic biopsy samples of PD patients and control group Clinical 2019 Higher expression of the endotoxin-specific ligand TLR4, CD3 + T cells, and cytokine expression, and dysbiosis in colonic samples of PD patients TLR4 contributes to neuroinflammation and intestine inflammation in PD [98]
Using flow cytometry and western blot to find TLR2 and TLR4 expression in blood and brain of PD patients Clinical 2014 Increased expression of TLR2 and TLR4 in circulating monocytes, and increased TLR4 in B cells and caudate and putamen brain regions in PD patients TLR2 and TLR4 are modulated in the blood and brain of PD patients [150]
Comparing single nucleotide polymorphisms of TLR9 between PD patients and control group Clinical 2020 The DNA analysis of samples showed that rs352140 T allele of TLR9 was associated with reduced risk of PD TLR9 SNPs are associated with PD risk [154]
Comparing the WT and TLR4-deficient MPTP-induced mice brain regions by Fourier Transform Infrared Animal/in vitro 2017 WT mice were more prone to dopaminergic neuron degeneration following MPTP TLR4 play roles in biochemical changes relating to neurodegeneration in MPTP-induced animal model of PD [100]
In vivo model of PD using MPTP mice Animal/in vitro 2019 The absence of TLR4 prevented inflammation, cytokine production, dopamine depletion, modulated inflammasome pathway, and reduced astrogliosis, and α-synuclein-positive neurons TLR4 may be an attractive therapeutic target for reversing PD-like manifestations in PD animal model [155]
Male rats were given intra-striatal injections of 6-hydroxydopamine, rotenone, LPS, or Poly I:C, and the expression of TLR3 and TLR4 were examined Animal/in vitro 2017 Prominent changes in TLR3 and TLR4 expression in the inflamed striatum of all rats TLR3 and TLR4 play significant roles in inducing PD-like symptoms in 6OHDP-induced animal model of PD [102]
Comparing the behavior and biochemistry of striatal and SN brain regions of MPTP-induced wild-type mice and MPTP-induced TLR4-deficient mice Animal/in vitro 2019 TLR4 deficiency significantly improved MPTP-induced motor deficits, attenuated α-synuclein reduction, and improved neuroinflammation TLR4 contributes significantly to PD-like symptoms in MPTP-induced animal model of PD [156]
Comparing α-synuclein-treated TLR2 knockout mice and WT mice microglia Animal/in vitro 2013 Extracellular oligomeric α-synuclein released from neuron cells serve as a ligand for TLR2 and initiate an inflammatory response TLR2 and oligomeric α-synuclein both might have the potential to serve as novel therapeutic targets in PD [157]
Comparing TLR2 knockout and WT mice Animal/in vitro 2016 Neuron-derived α-synuclein activates TLR2 and leads to neuroinflammation-induced neurodegeneration TLR2 is an essential molecule mediating non-cell-autonomous neurotoxic effects of α-synuclein in the genetic animal model of PD [158]
Comparing A53T + TLR2 + / + and A53T + TLR2 knockout mice Animal/in vitro 2016 Inactivating TLR2 led to phagocytosis activation and decreased α-synuclein aggregation
Moreover, activation of TLR2 led to reduced phagocytosis activity by regulating AKT/mTOR
TLR2 plays a significant role in the phagocytosis activities of microglia [90]
  1. TLR toll-like receptor, WT mice wild-type mice, PD Parkinson’s disease, SNP single nucleotide polymorphism, MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, SN substantia nigra, LPS lipopolysaccharide, Poly I:C polyinosinic:polycytidylic acid, PDD PD with dementia, PDND PD with no dementia, iLBD incidental Lewy body disease