2024-03-29T08:29:04Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1231512022-11-16T16:28:03Zcom_10261_64com_10261_1com_10261_134col_10261_317col_10261_387
Preconditioning of microglia by α-synuclein strongly affects the response induced by toll-like receptor (TLR) stimulation
Roodveldt, Cintia
Labrador-Garrido, Adahir
Lachaud, Christian C.
Fernández Montesinos, Rafael
Benítez-Rondán, Alicia
Hmadcha, Abdelkrim
Pozo, David
Ministerio de Ciencia e Innovación (España)
Instituto de Salud Carlos III
European Commission
Junta de Andalucía
Ministerio de Educación, Cultura y Deporte (España)
Wellcome Trust
Biotechnology and Biological Sciences Research Council (UK)
Parkinson's Disease Society (UK)
Roodveldt, Cintia et al.
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 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) αSyn 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 αSyn by augmenting IL-6, MCP-1/CCL2 or IP-10/CXCL10 secretion levels. Furthermore, we report a skewing of αSyn-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 αSyn-primed microglia after stimulation with these particular TLR agonists. Overall, we report a remarkable impact of non-aggregated αSyn presensitization of microglia on TLR-mediated immunity, a phenomenon that could contribute to triggering the onset of sporadic α-synuclein-related neuropathologies. © 2013 Roodveldt et al.
2015-10-08T09:12:06Z
2015-10-08T09:12:06Z
2013-11-13
2015-10-08T09:12:06Z
artículo
PLoS ONE 8(11): e79160 (2013)
http://hdl.handle.net/10261/123151
10.1371/journal.pone.0079160
http://dx.doi.org/10.13039/501100004837
http://dx.doi.org/10.13039/501100004587
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/501100003176
http://dx.doi.org/10.13039/100004440
http://dx.doi.org/10.13039/501100000268
http://dx.doi.org/10.13039/501100011011
24236103
eng
Publisher's version
http://dx.doi.org/10.1371/journal.pone.0079160
Sí
http://creativecommons.org/licenses/by/4.0/
openAccess
Public Library of Science