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Preconditioning of microglia by ?-synuclein strongly affects the response induced by toll-like receptor (TLR) stimulation.

ABSTRACT: In recent years, it has become accepted that ?-synuclein (?Syn) has a key role in the microglia-mediated neuroinflammation, which accompanies the development of Parkinson's disease and other related disorders, such as Dementia with Lewy Bodies and Alzheimer's disease. Nevertheless, the cellular and molecular mechanisms underlying its pathological actions, especially in the sporadic forms of the diseases, are not completely understood. Intriguingly, several epidemiological and animal model studies have revealed a link between certain microbial infections and the onset or progression of sporadic forms of these neurodegenerative disorders. In this work, we have characterized the effect of toll-like receptor (TLR) stimulation on primary murine microglial cultures and analysed the impact of priming cells with extracellular wild-type (Wt) ?Syn on the subsequent TLR stimulation of cells with a set of TLR ligands. By assaying key interleukins and chemokines we report that specific stimuli, in particular Pam3Csk4 (Pam3) and single-stranded RNA40 (ssRNA), can differentially affect the TLR2/1- and TLR7-mediated responses of microglia when pre-conditioned with ?Syn by augmenting IL-6, MCP-1/CCL2 or IP-10/CXCL10 secretion levels. Furthermore, we report a skewing of ?Syn-primed microglia stimulated with ssRNA (TLR7) or Pam3 (TLR2/1) towards intermediate but at the same time differential, M1/M2 phenotypes. Finally, we show that the levels and intracellular location of activated caspase-3 protein change significantly in ?Syn-primed microglia after stimulation with these particular TLR agonists. Overall, we report a remarkable impact of non-aggregated ?Syn pre-sensitization of microglia on TLR-mediated immunity, a phenomenon that could contribute to triggering the onset of sporadic ?-synuclein-related neuropathologies.

SUBMITTER: Roodveldt C

PROVIDER: S-EPMC3827304 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Preconditioning of microglia by α-synuclein strongly affects the response induced by toll-like receptor (TLR) stimulation.

Roodveldt Cintia C Labrador-Garrido Adahir A Gonzalez-Rey Elena E Lachaud Christian C CC Guilliams Tim T Fernandez-Montesinos Rafael R Benitez-Rondan Alicia A Robledo Gema G Hmadcha Abdelkrim A Delgado Mario M Dobson Christopher M CM Pozo David D

PloS one 20131113 11

In recent years, it has become accepted that α-synuclein (αSyn) has a key role in the microglia-mediated neuroinflammation, which accompanies the development of Parkinson's disease and other related disorders, such as Dementia with Lewy Bodies and Alzheimer's disease. Nevertheless, the cellular and molecular mechanisms underlying its pathological actions, especially in the sporadic forms of the diseases, are not completely understood. Intriguingly, several epidemiological and animal model studie ...[more]

PMID: 24236103

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Project description:BACKGROUND: Toll-like receptors (TLRs) are a major class of pattern recognition receptors (PRRs) expressed in the cell surface or membrane compartments of immune and non-immune cells. TLRs are encoded by a multigene family and represent the first line of defense against pathogens by detecting foreigner microbial molecular motifs, the pathogen-associated molecular patterns (PAMPs). TLRs are also important by triggering the adaptive immunity in vertebrates. They are characterized by the presence of leucine-rich repeats (LRRs) in the ectodomain, which are associated with the PAMPs recognition. The direct recognition of different pathogens by TLRs might result in different evolutionary adaptations important to understand the dynamics of the host-pathogen interplay. Ten mammal TLR genes, viral (TLR3, 7, 8, 9) and non-viral (TLR1-6, 10), were selected to identify signatures of positive selection that might have been imposed by interacting pathogens and to clarify if viral and non-viral TLRs might display different patterns of molecular evolution. RESULTS: By using Maximum Likelihood approaches, evidence of positive selection was found in all the TLRs studied. The number of positively selected codons (PSC) ranged between 2-26 codons (0.25%-2.65%) with the non-viral TLR4 as the receptor with higher percentage of positively selected codons (2.65%), followed by the viral TLR8 (2.50%). The results indicated that viral and non-viral TLRs are similarly under positive selection. Almost all TLRs have at least one PSC located in the LRR ectodomain which underlies the importance of the pathogen recognition by this region. CONCLUSIONS: Our results are not in line with previous studies on primates and birds that identified more codons under positive selection in non-viral TLRs. This might be explained by the fact that both primates and birds are homogeneous groups probably being affected by only a restricted number of related viruses with equivalent motifs to be recognized. The analyses performed in this work encompassed a large number of species covering some of the most representative mammalian groups - Artiodactyla, Rodents, Carnivores, Lagomorphs and Primates - that are affected by different families of viruses. This might explain the role of adaptive evolution in shaping viral TLR genes.

Dataset Information

Preconditioning of microglia by ?-synuclein strongly affects the response induced by toll-like receptor (TLR) stimulation.

Publications

Preconditioning of microglia by α-synuclein strongly affects the response induced by toll-like receptor (TLR) stimulation.

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