Toll‐like receptor 4 is required for α‐synuclein dependent activation of microglia and astroglia

GLIA - Tập 61 Số 3 - Trang 349-360 - 2013
Lisa Fellner1,2, Regina Irschick3, Kathrin Schanda1, Markus Reindl1, Lars Klimaschewski3, Werner Poewe1, Gregor K. Wenning1,2, Nadia Stefanova1,2
1Department of Neurology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
2Division of Neurobiology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
3Division of Neuroanatomy, Department of Anatomy, Histology and Embryology, Innsbruck Medical University, Muellerstrasse 59, 6020 Innsbruck, Austria

Tóm tắt

AbstractAlpha‐synucleinopathies (ASP) are neurodegenerative disorders, characterized by accumulation of misfolded α‐synuclein, selective neuronal loss, and extensive gliosis. It is accepted that microgliosis and astrogliosis contribute to the disease progression in ASP. Toll‐like receptors (TLRs) are expressed on cells of the innate immune system, including glia, and TLR4 dysregulation may play a role in ASP pathogenesis. In this study we aimed to define the involvement of TLR4 in microglial and astroglial activation induced by different forms of α‐synuclein (full length soluble, fibrillized, and C‐terminally truncated). Purified primary wild type (TLR4+/+) and TLR4 deficient (TLR4−/−) murine microglial and astroglial cell cultures were treated with recombinant α‐synuclein and phagocytic activity, NFκB nuclear translocation, cytokine release, and reactive oxygen species (ROS) production were measured. We show that TLR4 mediates α‐synuclein‐induced microglial phagocytic activity, pro‐inflammatory cytokine release, and ROS production. TLR4−/− astroglia present a suppressed pro‐inflammatory response and decreased ROS production triggered by α‐synuclein treatment. However, the uptake of α‐synuclein by primary astroglia is not dependent on TLR4 expression. Our results indicate the C‐terminally truncated form as the most potent inductor of TLR4‐dependent glial activation. The current findings suggest that TLR4 plays a modulatory role on glial pro‐inflammatory responses and ROS production triggered by α‐synuclein. In contrast to microglia, the uptake of alpha‐synuclein by astroglia is not dependent on TLR4. Our data provide novel insights into the mechanisms of α‐synuclein‐induced microglial and astroglial activation which may have an impact on understanding the pathogenesis of ASP. © 2012 Wiley Periodicals, Inc.

Từ khóa


Tài liệu tham khảo

10.1016/S0065-2776(01)78001-7

10.1371/journal.pone.0007114

10.1523/JNEUROSCI.0976-10.2010

10.1016/j.neures.2010.12.020

10.1016/j.jmb.2005.10.071

10.1523/JNEUROSCI.1799-06.2006

Baba M, 1998, Aggregation of alpha‐synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies, Am J Pathol, 152, 879

10.1021/la063048k

10.1002/glia.10256

10.1093/jnen/61.11.1013

10.1002/glia.20117

10.1074/jbc.M108414200

10.1021/bi991447r

10.3109/08820139.2011.561904

10.1016/j.brainresrev.2010.01.001

10.1007/s00401-011-0833-z

Gai WP, 1999, Alpha‐synuclein immunoisolation of glial inclusions from multiple system atrophy brain tissue reveals multiprotein components, J Neurochem, 73, 2093, 10.1046/j.1471-4159.1999.02093.x

10.1523/JNEUROSCI.23-04-01228.2003

10.1017/S1462399409001148

10.1212/01.WNL.0000078192.95645.E6

10.1016/j.nbd.2005.08.002

10.1016/j.neuroscience.2007.02.055

10.1002/glia.21094

10.1002/mds.23455

10.1016/j.parkreldis.2004.10.013

10.1007/s00401-004-0919-y

10.1002/jnr.20767

10.1096/fj.06-6183com

10.1016/j.neurobiolaging.2006.11.013

10.1016/j.tins.2008.11.005

10.4049/jimmunol.0903480

10.4161/oxim.3.4.12809

10.1016/j.bbrc.2008.05.045

10.1074/jbc.M109.081125

10.1002/glia.20928

10.1016/j.neurobiolaging.2007.08.018

10.1021/pr0701512

10.1126/science.1110647

10.1016/j.brainresrev.2008.09.001

10.1093/brain/awh303

10.1002/glia.20691

10.1111/j.1750-3639.2012.00597.x

10.1038/nn.2923

10.1016/j.nurt.2010.07.001

10.1523/JNEUROSCI.3158-09.2009

10.1007/s11481-008-9100-z

10.1186/1742-2094-8-44

10.1371/journal.pone.0013481

10.1016/j.cell.2009.01.038

10.1002/ana.21685

10.1523/JNEUROSCI.3527-05.2005

10.1016/j.neuroscience.2004.09.053

10.1016/j.ajpath.2011.04.013

10.1002/jnr.1171

10.1002/mds.21671

10.1002/jnr.10662

10.1016/S0301-0082(98)00083-5

10.1002/glia.10154

10.1016/j.neurobiolaging.2007.04.006

10.1007/PL00007400

10.1073/pnas.0602841103

10.1371/journal.pone.0005515

10.1096/fj.04-2751com

Thông tin
Thông tin xuất bản

GLIA

Tập 61 Số 3

349-360

Thông tin tác giả