Inhibition of MyD88 Signaling Skews Microglia/Macrophage Polarization and Attenuates Neuronal Apoptosis in the Hippocampus After Status Epilepticus in Mice.

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  • Author(s): Liu JT;Liu JT;Liu JT;Liu JT; Wu SX; Wu SX; Zhang H; Zhang H; Kuang F; Kuang F
  • Source:
    Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics [Neurotherapeutics] 2018 Oct; Vol. 15 (4), pp. 1093-1111.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Springer Country of Publication: United States NLM ID: 101290381 Publication Model: Print Cited Medium: Internet ISSN: 1878-7479 (Electronic) Linking ISSN: 18787479 NLM ISO Abbreviation: Neurotherapeutics Subsets: MEDLINE
    • Publication Information:
      Publication: 2011- : New York : Springer
      Original Publication: Orlando, FL : Elsevier, c2007-
    • Subject Terms:
      Apoptosis/*physiology ; Hippocampus/*metabolism ; Macrophages/*pathology ; Microglia/*pathology ; Myeloid Differentiation Factor 88/*antagonists & inhibitors ; Neurons/*pathology ; Signal Transduction/*genetics ; Status Epilepticus/*pathology; Animals ; Apoptosis/genetics ; Cell Polarity/genetics ; Cytokines/metabolism ; Disease Models, Animal ; Female ; Gene Expression Regulation, Archaeal/drug effects ; Gene Expression Regulation, Archaeal/genetics ; Hippocampus/pathology ; In Situ Nick-End Labeling ; Lithium/toxicity ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myeloid Differentiation Factor 88/chemistry ; Myeloid Differentiation Factor 88/deficiency ; Peptides/therapeutic use ; Pilocarpine/toxicity ; Status Epilepticus/chemically induced ; Status Epilepticus/genetics ; Toll-Like Receptor 4/metabolism
    • Abstract:
      Inflammation is implicated in epileptogenesis. Activated microglia and macrophages (MG/MΦ) are found in the brains of patients with epilepsy-related diseases and animal models of epilepsy. It is not yet known how the MG/MΦ activation phenotype affects pathological changes in the brain after a single seizure. In this study, we had 2 main purposes: first, to characterize post-status epilepticus (SE) inflammation by tracking MG/MΦ polarization, and, second, to explore the role of an innate immune receptor adaptor protein, namely, myeloid differentiation primary response gene 88 (MyD88), in the induction of SE in a mouse model. A lithium-pilocarpine model of seizure conditions was generated in C57BL/6 mice. The intensity and distribution of MG/MΦ polarization were tracked by fluorescent immunohistochemistry and Western blotting for the polarization markers inducible nitrogen oxygenized synthase, arginase-1, CD163, and mannose receptor. We observed steadily increasing M1 MG/MΦ along with MyD88 signal upregulation after SE in the hippocampi of mice, whereas the M2 marker arginase-1 was localized mainly in astrocytes rather than in MG/MΦ. Inhibition or gene knockout of MyD88 reduced M1 MG/MΦ and gliosis although increasing M2 MG/MΦ in the hippocampi of SE mice. MyD88 inhibition also augmented glutamate transporter 1 expression and reduced N-methyl-D-aspartate receptor NR1 subunit expression in the hippocampus to protect pyramidal neurons from apoptosis. These data suggest that MG/MΦ polarization after SE impacts the pathological outcome of the hippocampus via MyD88 signaling and point to MyD88 as a potential neuroprotective target for epilepsy therapy.
    • References:
      Br J Pharmacol. 2016 Feb;173(4):649-65. (PMID: 25800044)
      J Neurosci. 2009 Oct 28;29(43):13435-44. (PMID: 19864556)
      Trends Neurosci. 2013 Mar;36(3):174-84. (PMID: 23298414)
      Behav Brain Res. 2012 Feb 1;227(1):36-42. (PMID: 22051943)
      J Neurochem. 2002 Jul;82(2):269-82. (PMID: 12124428)
      Exp Neurol. 2017 Sep;295:23-35. (PMID: 28529112)
      J Neurosci. 2015 Apr 1;35(13):5187-201. (PMID: 25834045)
      J Exp Med. 2015 Apr 6;212(4):435-45. (PMID: 25753580)
      J Neurosci. 2010 Jan 13;30(2):739-48. (PMID: 20071539)
      Nat Med. 2010 Apr;16(4):413-9. (PMID: 20348922)
      Shock. 2006 Jan;25(1):4-11. (PMID: 16369179)
      Hum Mol Genet. 2015 Sep 1;24(17):4780-91. (PMID: 26034136)
      Epilepsy Res. 2016 Jan;119:77-85. (PMID: 26688426)
      Nat Rev Neurol. 2015 Jan;11(1):56-64. (PMID: 25385337)
      Glia. 2006 Apr 15;53(6):583-92. (PMID: 16419089)
      Stroke. 2012 Nov;43(11):3063-70. (PMID: 22933588)
      Sci Rep. 2016 Jun 17;6:28188. (PMID: 27312666)
      Neurobiol Dis. 2005 Mar;18(2):375-84. (PMID: 15686966)
      Neurocrit Care. 2014 Jun;20(3):502-13. (PMID: 24519081)
      Exp Neurol. 2013 Jun;244:11-21. (PMID: 21985866)
      Exp Brain Res. 2013 Apr;226(2):153-63. (PMID: 23392471)
      Lancet Neurol. 2006 Apr;5(4):317-22. (PMID: 16545748)
      Brain Behav Immun. 2011 Oct;25(7):1281-9. (PMID: 21473909)
      Exp Neurol. 2003 Jul;182(1):21-34. (PMID: 12821374)
      Epilepsia. 2015 Jun;56(6):895-905. (PMID: 25847097)
      Protein Cell. 2013 Jan;4(1):27-39. (PMID: 22996173)
      Exp Ther Med. 2014 Jul;8(1):73-78. (PMID: 24944600)
      J Cereb Blood Flow Metab. 2013 Dec;33(12):1864-74. (PMID: 23942366)
      Ann Neurol. 2016 Jul;80(1):35-45. (PMID: 27129611)
      J Cell Biol. 2016 Dec 5;215(5):719-734. (PMID: 27920126)
      Pediatrics. 2001 Oct;108(4):E63. (PMID: 11581471)
      Acta Neuropsychiatr. 2017 Feb;29(1):1-16. (PMID: 27692004)
      Trends Pharmacol Sci. 2015 Jun;36(6):395-405. (PMID: 25930708)
      Evid Based Complement Alternat Med. 2012;2012:591298. (PMID: 22675384)
      Nat Commun. 2014 Dec 05;5:5648. (PMID: 25476696)
      Epilepsy Behav. 2011 Dec;22(4):617-40. (PMID: 22056342)
      Brain Behav Immun. 2012 Aug;26(6):880-5. (PMID: 22401992)
      J Cereb Blood Flow Metab. 2008 May;28(5):927-38. (PMID: 18000511)
      J Biol Chem. 1994 Apr 29;269(17):12589-93. (PMID: 7513691)
      Brain Res. 2012 May 9;1453:77-86. (PMID: 22483960)
      Mol Neurobiol. 2016 Jan;53(1):1-7. (PMID: 25394384)
      Epilepsia. 2010 Mar;51(3):454-64. (PMID: 19845729)
      Clin Neurol Neurosurg. 2006 Jul;108(5):433-9. (PMID: 16225987)
      Epilepsia. 2005 Nov;46(11):1724-43. (PMID: 16302852)
      Epilepsy Res. 2002 Apr;49(2):109-20. (PMID: 12049799)
      Glia. 2012 Aug;60(8):1215-26. (PMID: 22592998)
      J Neurosci. 2005 Jul 20;25(29):6734-44. (PMID: 16033883)
      Eur J Neurosci. 2013 Apr;37(7):1193-202. (PMID: 23311438)
      Trends Immunol. 2001 Feb;22(2):78-83. (PMID: 11286707)
      J Neurosci Res. 2014 Dec;92(12):1647-58. (PMID: 25044014)
      Glia. 2015 Mar;63(3):400-11. (PMID: 25327891)
      Brain Res. 2017 Feb 15;1657:120-129. (PMID: 27956120)
      J Neurosci. 2012 Jul 25;32(30):10117-28. (PMID: 22836247)
      J Cell Physiol. 2018 Sep;233(9):7022-7034. (PMID: 29380367)
      Acta Neuropathol. 2016 Feb;131(2):211-234. (PMID: 26423537)
      Nat Neurosci. 2016 Jul 26;19(8):987-91. (PMID: 27459405)
      Neuroscience. 2015 Aug 27;302:59-73. (PMID: 25463515)
      Neuron. 2008 Apr 24;58(2):168-78. (PMID: 18439402)
      Br J Pharmacol. 1998 Oct;125(3):584-90. (PMID: 9806344)
    • Grant Information:
      81671217 International National Natural Science Foundation of China; 81271433 International National Natural Science Foundation of China
    • Contributed Indexing:
      Keywords: Hippocampus; Microglia/macrophage polarization; MyD88; Neuroinflammation; Status epilepticus
    • Accession Number:
      0 (Cytokines)
      0 (Myd88 protein, mouse)
      0 (Myeloid Differentiation Factor 88)
      0 (Peptides)
      0 (Tlr4 protein, mouse)
      0 (Toll-Like Receptor 4)
      01MI4Q9DI3 (Pilocarpine)
      9FN79X2M3F (Lithium)
    • Publication Date:
      Date Created: 20180817 Date Completed: 20190312 Latest Revision: 20240204
    • Publication Date:
      20240205
    • Accession Number:
      PMC6277303
    • Accession Number:
      10.1007/s13311-018-0653-0
    • Accession Number:
      30112701