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Toll-Like Receptor 2 Deficiency Shifts PrP106-126-Induced Microglial Activation from a Neurotoxic to a Neuroprotective Phenotype

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Abstract

Prion diseases are fatal neurodegenerative diseases characterized by spongiform change, neuronal loss, and gliosis involving microglial activation in the central nervous system. Microglial activation is thought to play a key role in the pathogenesis of prion disease; however, the molecular mechanisms underlying prion-induced microglial activation are not well understood. The present study underlines the importance of toll-like receptor (TLR)-2 in mediating PrP106-126-induced microglial activation. We found that PrP106-126 induced expression of proinflammatory molecules and TLR2 in microglial cells; however, functional blocking antibodies against TLR2 suppressed PrP106-126-induced expression of proinflammatory molecules. PrP106-126-induced expression of proinflammatory molecules was also reduced in microglial cells isolated from TLR2−/− mice compared to those isolated from wild-type mice. Consistent with the importance of nuclear factor kappa B (NF-κB) mediating TLR functions, NF-κB inhibition also inhibited PrP106-126-induced expression of proinflammatory molecules. To better understand the effect of TLR2 deficiency on active microglial cells, we studied the expression of Arg1 and Mrc1 and anti-inflammatory cytokines, which indicated that TLR2 deficiency in microglial cells results in a shift from neurotoxic to neuroprotective phenotype. Taken together, our results indicate that the TLR2 signaling pathway mediates PrP106-126-induced microglial activation and potentially reveal new therapeutic strategies for prion diseases that modulate TLR2 signaling.

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Abbreviations

GSS:

Gerstmann-Sträussler syndrome

CJD:

Creutzfeldt-Jakob disease

CNS:

Central nervous system

PD:

Parkinson’s disease

MS:

Multiple sclerosis

AD:

Alzheimer’s disease

TLR:

Toll-like receptor

KO:

Knockout

WT:

Wild type

Aβ:

Amyloid β

SCC:

Strongly connected component

MAPK:

Mitogen-activated protein kinase

ERK:

Extracellular signal-regulated kinase

mFPR2:

Formyl peptide receptor 2

miR:

mRNA

RAGE:

Receptor for advanced glycation end products

NF-κB:

Nuclear factor kappa B

CCK-8:

Cell counting Kit-8

DMEM:

Dulbecco’s modified Eagle’s medium

cDNA:

Complementary DNA

qPCR:

Quantitative polymerase chain reaction

ROS:

Reactive oxygen species

TNF:

Tumor necrosis factor

IL:

Interleukin

iNOS:

Inducible isoform of nitric oxide synthase

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

TBS:

Tris-buffered saline

ECF:

Chemifluorescence

ThT:

Thioflavine-T

PDTC:

Pyrrolidine dithiocarbamate

Arg:

Arginase

Mrc:

Macrophage mannose receptor

MyD88:

Myeloid differentiation factor 88

TGF:

Transforming growth factor

PAMPs:

Pathogen-associated molecular pattern molecules

DAMPs:

Damage-associated molecular pattern molecules

NTF:

Neurotrophic factors

TIRAP:

TIR domain-containing adaptor protein

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Acknowledgments

This work was supported by the National “Twelfth Five-Year” Plan for Science & Technology Support (Project No. 2012AA101302), MoSTRCUK international cooperation project (Project No. 2013DFG32500), the National Natural Science Foundation (Project No. 31172293, No. 31272532), Chinese Universities Scientific Fund (Project No. 2013QT004), and CAU Foreign Experts Major Projects (Project No. 2012Z018)

Conflict of interest

The authors declare no financial or commercial conflicts of interest.

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Authors and Affiliations

  1. State Key Lab of Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, 100193, Beijing, People’s Republic of China

    Jihong Wang, Deming Zhao, Bo Pan, Yongyao Fu, Fushan Shi, Mohammed Kouadir, Lifeng Yang, Xiaomin Yin & Xiangmei Zhou

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  1. Jihong Wang
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  2. Deming Zhao
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  3. Bo Pan
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  6. Mohammed Kouadir
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  7. Lifeng Yang
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  8. Xiaomin Yin
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  9. Xiangmei Zhou
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Corresponding author

Correspondence to Xiangmei Zhou.

Additional information

Jihong Wang and Deming Zhao contributed equally to this work.

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Wang, J., Zhao, D., Pan, B. et al. Toll-Like Receptor 2 Deficiency Shifts PrP106-126-Induced Microglial Activation from a Neurotoxic to a Neuroprotective Phenotype. J Mol Neurosci 55, 880–890 (2015). https://doi.org/10.1007/s12031-014-0442-0

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