Microglia mediate neurocognitive deficits by eliminating C1q-tagged synapses in sepsis-associated encephalopathy.
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
26 05 2023
26 05 2023
Historique:
medline:
29
5
2023
pubmed:
26
5
2023
entrez:
26
5
2023
Statut:
ppublish
Résumé
Sepsis-associated encephalopathy (SAE) is a severe and frequent complication of sepsis causing delirium, coma, and long-term cognitive dysfunction. We identified microglia and C1q complement activation in hippocampal autopsy tissue of patients with sepsis and increased C1q-mediated synaptic pruning in a murine polymicrobial sepsis model. Unbiased transcriptomics of hippocampal tissue and isolated microglia derived from septic mice revealed an involvement of the innate immune system, complement activation, and up-regulation of lysosomal pathways during SAE in parallel to neuronal and synaptic damage. Microglial engulfment of C1q-tagged synapses could be prevented by stereotactic intrahippocampal injection of a specific C1q-blocking antibody. Pharmacologically targeting microglia by PLX5622, a CSF1-R inhibitor, reduced C1q levels and the number of C1q-tagged synapses, protected from neuronal damage and synapse loss, and improved neurocognitive outcome. Thus, we identified complement-dependent synaptic pruning by microglia as a crucial pathomechanism for the development of neuronal defects during SAE.
Identifiants
pubmed: 37235660
doi: 10.1126/sciadv.abq7806
pmc: PMC10219600
doi:
Substances chimiques
Complement C1q
80295-33-6
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
eabq7806Références
Mol Immunol. 2015 Feb;63(2):456-63
pubmed: 25451975
Cell Rep. 2021 Jul 27;36(4):109433
pubmed: 34273271
Neuropathol Appl Neurobiol. 2019 Apr;45(3):278-290
pubmed: 29804289
F1000Res. 2016 Jul 15;5:1717
pubmed: 27830058
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Methods. 2001 Dec;25(4):402-8
pubmed: 11846609
J Neurol Neurosurg Psychiatry. 2019 Aug;90(8):870-881
pubmed: 30967444
Science. 2005 May 27;308(5726):1314-8
pubmed: 15831717
Brain. 2023 Feb 13;146(2):600-611
pubmed: 35259208
Ann Neurol. 2015 Jun;77(6):1007-26
pubmed: 25727254
JAMA. 2010 Oct 27;304(16):1787-94
pubmed: 20978258
Cell Rep. 2019 Dec 3;29(10):3087-3100.e7
pubmed: 31801075
Mol Neurobiol. 2013 Feb;47(1):394-8
pubmed: 23054679
F1000Res. 2020 Jul 15;9:
pubmed: 33564394
Bioinformatics. 2014 Apr 1;30(7):923-30
pubmed: 24227677
J Neuroinflammation. 2017 Mar 6;14(1):48
pubmed: 28264694
Annu Rev Genet. 2019 Dec 3;53:263-288
pubmed: 31518519
Science. 2011 Sep 9;333(6048):1456-8
pubmed: 21778362
PLoS One. 2019 Jan 24;14(1):e0211184
pubmed: 30677080
Immunity. 2020 Nov 17;53(5):1033-1049.e7
pubmed: 33049219
Nat Protoc. 2013 Dec;8(12):2531-7
pubmed: 24263092
Neuron. 2018 Dec 19;100(6):1322-1336.e7
pubmed: 30392797
J Neuroimmunol. 2017 Feb 15;303:90-98
pubmed: 28087076
Nucleic Acids Res. 2002 Jan 1;30(1):207-10
pubmed: 11752295
EMBO J. 2020 Aug 17;39(16):e105380
pubmed: 32657463
Intensive Care Med. 2017 Aug;43(8):1075-1084
pubmed: 28466149
J Surg Res. 2011 Sep;170(1):e123-34
pubmed: 21737102
Proc Natl Acad Sci U S A. 2020 Sep 22;117(38):23336-23338
pubmed: 32900927
EMBO J. 2019 Sep 2;38(17):e101064
pubmed: 31359456
Cell. 2013 Dec 19;155(7):1596-609
pubmed: 24360280
Genome Biol. 2014;15(12):550
pubmed: 25516281
Science. 2021 Sep 10;373(6560):eabj2685
pubmed: 34516796
Cell Mol Immunol. 2021 Feb;18(2):250-258
pubmed: 33437050
Neuron. 2014 Apr 16;82(2):380-97
pubmed: 24742461
Science. 2016 May 6;352(6286):712-716
pubmed: 27033548
PLoS One. 2010 Nov 15;5(11):e13984
pubmed: 21085593
J Clin Med. 2020 Mar 05;9(3):
pubmed: 32150970
Nat Rev Immunol. 2022 Jul;22(7):444-458
pubmed: 34764472
BMJ Open. 2020 Jun 23;10(6):e036527
pubmed: 32580988
Nat Neurosci. 2013 Dec;16(12):1896-905
pubmed: 24162652
PLoS One. 2012;7(2):e31814
pubmed: 22457705
Nat Commun. 2019 Aug 21;10(1):3758
pubmed: 31434879
Nature. 2021 Sep;597(7878):709-714
pubmed: 34497421
Neurobiol Dis. 2004 Feb;15(1):40-6
pubmed: 14751769
Front Neurol. 2015 Jun 11;6:136
pubmed: 26124746
Genome Res. 2003 Nov;13(11):2498-504
pubmed: 14597658
Immun Ageing. 2019 Jul 30;16:18
pubmed: 31384283
Front Cell Infect Microbiol. 2021 Nov 15;11:717689
pubmed: 34869052
Mol Psychiatry. 2019 Oct;24(10):1533-1548
pubmed: 29875474
J Immunol. 2019 Dec 1;203(11):2979-2989
pubmed: 31619539
Nature. 2008 Nov 6;456(7218):53-9
pubmed: 18987734
J Neurosci. 2020 Apr 1;40(14):2960-2974
pubmed: 32094203
MAbs. 2014 Jan-Feb;6(1):204-18
pubmed: 24262918
Front Immunol. 2022 Aug 02;13:965305
pubmed: 35983035
Science. 2016 Aug 19;353(6301):777-83
pubmed: 27540165
Methods Mol Biol. 2019;2034:217-230
pubmed: 31392688
J Neurochem. 2021 Aug;158(3):621-639
pubmed: 33608912
Nat Med. 2017 Sep 8;23(9):1018-1027
pubmed: 28886007
J Neurol Neurosurg Psychiatry. 2013 Jan;84(1):62-9
pubmed: 23134661
J Neuroinflammation. 2022 Jan 4;19(1):3
pubmed: 34983562
EMBO Rep. 2018 Nov;19(11):
pubmed: 30206190
Trends Immunol. 2020 Sep;41(9):771-784
pubmed: 32792173
PLoS Biol. 2020 Jul 14;18(7):e3000410
pubmed: 32663219
J Neurosci. 2014 Jun 18;34(25):8546-56
pubmed: 24948809
J Neurochem. 2021 Nov;159(3):525-542
pubmed: 34379806
Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):6303-6308
pubmed: 29844190
Science. 2020 Feb 7;367(6478):688-694
pubmed: 32029629
Am J Respir Crit Care Med. 2016 Feb 1;193(3):259-72
pubmed: 26414292
Cell Rep. 2018 Jan 2;22(1):149-162
pubmed: 29298417
J Neuroinflammation. 2007 Jan 15;4:4
pubmed: 17224051
Nat Rev Neurol. 2012 Oct;8(10):557-66
pubmed: 22986430