title: Toll-like receptor 2 deficiency shifts PrP106-126-induced microglial activation from a neurotoxic to a neuroprotective phenotype.
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.
authors.affiliation: 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, Wangjihong2007@hotmail.com.
authors.forename: Jihong
authors.initials: J
authors.lastname: Wang
authors.forename: Deming
authors.initials: D
authors.lastname: Zhao
authors.forename: Bo
authors.initials: B
authors.lastname: Pan
authors.forename: Yongyao
authors.initials: Y
authors.lastname: Fu
authors.forename: Fushan
authors.initials: F
authors.lastname: Shi
authors.forename: Mohammed
authors.initials: M
authors.lastname: Kouadir
authors.forename: Lifeng
authors.initials: L
authors.lastname: Yang
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Yin
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity*; D010641:Phenotype; D011328:Prions / Q000633:toxicity*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2 / Q000172:deficiency* / Q000235:genetics
chemical_list: D016207:Cytokines; C581013:MRC1 protein, mouse; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010446:Peptide Fragments; D011328:Prions; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; C082632:prion protein (106-126); C544448:Arg1 protein, mouse; D001119:Arginase