Preconditioning of microglia by α-synuclein strongly affects the response induced by toll-like receptor (TLR) stimulation.
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 pre-sensitization of microglia on TLR-mediated immunity, a phenomenon that could contribute to triggering the onset of sporadic α-synuclein-related neuropathologies.
CABIMER, Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain.
Cintia
C
Roodveldt
Adahir
A
Labrador-Garrido
Elena
E
Gonzalez-Rey
Christian C
CC
Lachaud
Tim
T
Guilliams
Rafael
R
Fernandez-Montesinos
Alicia
A
Benitez-Rondan
Gema
G
Robledo
Abdelkrim
A
Hmadcha
Mario
M
Delgado
Christopher M
CM
Dobson
David
D
Pozo
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D001412:Bacillus subtilis; D053148:Caspase 3 / Q000378:metabolism; D016764:Cell Polarity; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D000077271:Imiquimod; D007113:Immunity, Innate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010457:Peptidoglycan / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000819:agonists* / Q000378:metabolism; D051844:alpha-Synuclein / Q000502:physiology*
D000634:Aminoquinolines; D016207:Cytokines; D010457:Peptidoglycan; D051193:Toll-Like Receptors; D051844:alpha-Synuclein; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3; C544448:Arg1 protein, mouse; D001119:Arginase; D011070:Poly I-C; D000077271:Imiquimod