Neuroscience Bulletin

, Volume 30, Issue 4, pp 645–654 | Cite as

Innate immune responses regulate morphogenesis and degeneration: roles of Toll-like receptors and Sarm1 in neurons

Review

Abstract

The central nervous system is recognized as an immunoprivileged site because peripheral immune cells do not typically enter it. Microglial cells are thought to be the main immune cells in brain. However, recent reports have indicated that neurons express the key players of innate immunity, including Toll-like receptors (TLRs) and their adaptor proteins (Sarm1, Myd88, and Trif), and may produce cytokines in response to pathogen infection. In the absence of an immune challenge, neuronal TLRs can detect intrinsic danger signals and modulate neuronal morphology and function. In this article, we review the recent findings on the involvement of TLRs and Sarm1 in controlling neuronal morphogenesis and neurodegeneration. Abnormal behaviors in TLR- and Sarm1-deficient mice are also discussed.

Keywords

axon cytokines dendrite innate immunity interleukin-6 Sarm1 toll-like receptor 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. [1]
    Kawai T, Akira S. TLR signaling. Cell Death Differ 2006, 13: 816–825.PubMedCrossRefGoogle Scholar
  2. [2]
    Dellacasagrande J. Ligands, cell-based models, and readouts required for Toll-like receptor action. Methods Mol Biol 2009, 517: 15–32.PubMedCrossRefGoogle Scholar
  3. [3]
    Kondo T, Kawai T, Akira S. Dissecting negative regulation of Toll-like receptor signaling. Trends Immunol 2012, 33: 449–458.PubMedCrossRefGoogle Scholar
  4. [4]
    Bsibsi M, Ravid R, Gveric D, van Noort JM. Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 2002, 61: 1013–1021.PubMedGoogle Scholar
  5. [5]
    Olson JK, Miller SD. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 2004, 173: 3916–3924.PubMedCrossRefGoogle Scholar
  6. [6]
    van Noort JM, Bsibsi M. Toll-like receptors in the CNS: implications for neurodegeneration and repair. Prog Brain Res 2009, 175: 139–148.PubMedCrossRefGoogle Scholar
  7. [7]
    Cunningham C. Microglia and neurodegeneration: The role of systemic inflammation. Glia 2013, 61: 71–90.PubMedCrossRefGoogle Scholar
  8. [8]
    Lafon M, Megret F, Lafage M, Prehaud C. The innate immune facet of brain: human neurons express TLR-3 and sense viral dsRNA. J Mol Neurosci 2006, 29: 185–194.PubMedCrossRefGoogle Scholar
  9. [9]
    Leow-Dyke S, Allen C, Denes A, Nilsson O, Maysami S, Bowie AG, et al. Neuronal Toll-like receptor 4 signaling induces brain endothelial activation and neutrophil transmigration in vitro. J Neuroinflammation 2012, 9: 230.PubMedCentralPubMedCrossRefGoogle Scholar
  10. [10]
    Kaul D, Habbel P, Derkow K, Kruger C, Franzoni E, Wulczyn FG, et al. Expression of Toll-like receptors in the developing brain. PLoS One 2012, 7: e37767.PubMedCentralPubMedCrossRefGoogle Scholar
  11. [11]
    Liu HY, Hong YF, Huang CM, Chen CY, Huang TN, Hsueh YP. TLR7 negatively regulates dendrite outgrowth through the Myd88-c-Fos-IL-6 pathway. J Neurosci 2013, 33: 11479–11493.PubMedCrossRefGoogle Scholar
  12. [12]
    Chen CY, Lin CW, Chang CY, Jiang ST, Hsueh YP. Sarm1, a negative regulator of innate immunity, interacts with syndecan-2 and regulates neuronal morphology. J Cell Biol 2011, 193: 769–784.PubMedCentralPubMedCrossRefGoogle Scholar
  13. [13]
    LinC W, Liu HY, Chen CY, Hsueh YP. Neuronally-expressed Sarm1 regulates expression of inflammatory and antiviral cytokines in brains. Innate Immun 2014, 20(2): 161–172.CrossRefGoogle Scholar
  14. [14]
    Kim Y, Zhou P, Qian L, Chuang JZ, Lee J, Li C, et al. MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival. J Exp Med 2007, 204: 2063–2074.PubMedCentralPubMedCrossRefGoogle Scholar
  15. [15]
    Czirr E, Wyss-Coray T. The immunology of neurodegeneration. J Clin Invest 2012, 122: 1156–1163.PubMedCentralPubMedCrossRefGoogle Scholar
  16. [16]
    Liu T, Gao YJ, Ji RR. Emerging role of Toll-like receptors in the control of pain and itch. Neurosci Bull 2012, 28: 131–144.PubMedCentralPubMedCrossRefGoogle Scholar
  17. [17]
    Kariko K, Weissman D, Welsh FA. Inhibition of toll-like receptor and cytokine signaling—a unifying theme in ischemic tolerance. J Cereb Blood Flow Metab 2004, 24: 1288–1304.PubMedCrossRefGoogle Scholar
  18. [18]
    Cavassani KA, Ishii M, Wen H, Schaller MA, Lincoln PM, Lukacs NW, et al. TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. J Exp Med 2008, 205: 2609–2621.PubMedCentralPubMedCrossRefGoogle Scholar
  19. [19]
    Green NM, Moody KS, Debatis M, Marshak-Rothstein A. Activation of autoreactive B cells by endogenous TLR7 and TLR3 RNA ligands. J Biol Chem 2012, 287: 39789–39799.PubMedCentralPubMedCrossRefGoogle Scholar
  20. [20]
    Lehmann SM, Kruger C, Park B, Derkow K, Rosenberger K, Baumgart J, et al. An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat Neurosci 2012, 15: 827–835.PubMedCrossRefGoogle Scholar
  21. [21]
    Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R, et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A 2012, 109: E2110–2116.PubMedCentralPubMedCrossRefGoogle Scholar
  22. [22]
    Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007, 9: 654–659.PubMedCrossRefGoogle Scholar
  23. [23]
    Lotvall J, Valadi H. Cell to cell signalling via exosomes through esRNA. Cell Adh Migr 2007, 1: 156–158.PubMedCentralPubMedCrossRefGoogle Scholar
  24. [24]
    Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 2002, 3: 196–200.PubMedCrossRefGoogle Scholar
  25. [25]
    Gorden KB, Gorski KS, Gibson SJ, Kedl RM, Kieper WC, Qiu X, et al. Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol 2005, 174: 1259–1268.PubMedCrossRefGoogle Scholar
  26. [26]
    Gorden KK, Qiu XX, Binsfeld CC, Vasilakos JP, Alkan SS. Cutting edge: activation of murine TLR8 by a combination of imidazoquinoline immune response modifiers and polyT oligodeoxynucleotides. J Immunol 2006, 177: 6584–6587.PubMedCrossRefGoogle Scholar
  27. [27]
    Gorden KK, Qiu X, Battiste JJ, Wightman PP, Vasilakos JP, Alkan SS. Oligodeoxynucleotides differentially modulate activation of TLR7 and TLR8 by imidazoquinolines. J Immunol 2006, 177: 8164–8170.PubMedCrossRefGoogle Scholar
  28. [28]
    Kim SJ, Park GH, Kim D, Lee J, Min H, Wall E, et al. Analysis of cellular and behavioral responses to imiquimod reveals a unique itch pathway in transient receptor potential vanilloid 1 (TRPV1)-expressing neurons. Proc Natl Acad Sci U S A 2011, 108: 3371–3376.PubMedCentralPubMedCrossRefGoogle Scholar
  29. [29]
    Lee J, Kim T, Hong J, Woo J, Min H, Hwang E, et al. Imiquimod enhances excitability of dorsal root ganglion neurons by inhibiting background (K(2P)) and voltage-gated (K(v)1.1 and K(v)1.2) potassium channels. Mol Pain 2012, 8: 2.PubMedCentralPubMedCrossRefGoogle Scholar
  30. [30]
    Cameron JS, Alexopoulou L, Sloane JA, DiBernardo AB, Ma Y, Kosaras B, et al. Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals. J Neurosci 2007, 27: 13033–13041.PubMedCrossRefGoogle Scholar
  31. [31]
    Ma Y, Li J, Chiu I, Wang Y, Sloane JA, Lu J, et al. Tolllike receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis. J Cell Biol 2006, 175: 209–215.PubMedCentralPubMedCrossRefGoogle Scholar
  32. [32]
    Lehmann SM, Rosenberger K, Kruger C, Habbel P, Derkow K, Kaul D, et al. Extracellularly delivered single-stranded viral RNA causes neurodegeneration dependent on TLR7. J Immunol 2012, 189: 1448–1458.PubMedCrossRefGoogle Scholar
  33. [33]
    Kawai T, Akira S. The ro le of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010, 11: 373–384.PubMedCrossRefGoogle Scholar
  34. [34]
    Kawai T, Akira S. Signali ng to NF-kappaB by Toll-like receptors. Trends Mol Med 2007, 13: 460–469.PubMedCrossRefGoogle Scholar
  35. [35]
    Walsh JG, Muruve DA, Power C. Inflammasomes in the CNS. Nat Rev Neurosci 2014, 15(2): 84–97.PubMedCrossRefGoogle Scholar
  36. [36]
    Latz E, Xiao TS, Stutz A. A ctivation and regulation of the inflammasomes. Nat Rev Immunol 2013, 13: 397–411.PubMedCrossRefGoogle Scholar
  37. [37]
    Gilmore JH, Fredrik Jarskog L, Vadlamudi S, Lauder JM. Prenatal infection and risk for schizophrenia: IL-1beta, IL-6, and TNFalpha inhibit cortical neuron dendrite development. Neuropsychopharmacology 2004, 29: 1221–1229.PubMedCrossRefGoogle Scholar
  38. [38]
    Kumar M, Verma S, Nerurkar VR. Pro-inflammatory cytokines derived from West Nile virus (WNV)-infected SK-N-SH cells mediate neuroinflammatory markers and neuronal death. J Neuroinflammation 2010, 7: 73.PubMedCentralPubMedCrossRefGoogle Scholar
  39. [39]
    Prehaud C, Megret F, Lafage M, Lafon M. Virus infection switches TLR-3-positive human neurons to become strong producers of beta interferon. J Virol 2005, 79: 12893–12904.PubMedCentralPubMedCrossRefGoogle Scholar
  40. [40]
    own T, Jeng D, Alexopoulou L, Tan J, Flavell RA. Microglia recognize double-stranded RNA via TLR3. J Immunol 2006, 176: 3804–3812.CrossRefGoogle Scholar
  41. [41]
    De Miranda J, Yaddanapudi K, Hornig M, Lipkin WI. Astrocytes recognize intracellular polyinosinic-polycytidylic acid via MDA-5. FASEB J 2009, 23: 1064–1071.PubMedCentralPubMedCrossRefGoogle Scholar
  42. [42]
    Gohlke JM, Griffith WC, Faustman EM. The role of cell death during neocortical neurogenesis and synaptogenesis: implications from a computational model for the rat and mouse. Brain Res Dev Brain Res 2004, 151: 43–54.PubMedCrossRefGoogle Scholar
  43. [43]
    Dekkers MP, Nikoletopoulou V, Barde YA. Cell biology in neuroscience: Death of developing neurons: new insights and implications for connectivity. J Cell Biol 2013, 203: 385–393.PubMedCentralPubMedCrossRefGoogle Scholar
  44. [44]
    Okun E, Griffioen K, Barak B, Roberts NJ, Castro K, Pita MA, et al. Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis. Proc Natl Acad Sci U S A 2010, 107: 15625–15630.PubMedCentralPubMedCrossRefGoogle Scholar
  45. [45]
    Okun E, Barak B, Saada-Madar R, Rothman SM, Griffioen KJ, Roberts N, et al. Evidence for a developmental role for TLR4 in learning and memory. PLoS One 2012, 7: e47522.PubMedCentralPubMedCrossRefGoogle Scholar
  46. [46]
    Khariv V, Pang K, Servatius RJ, David BT, Goodus MT, Beck KD, et al. Toll-like receptor 9 deficiency impacts sensory and motor behaviors. Brain Behav Immun 2013, 32: 164–172.PubMedCrossRefGoogle Scholar
  47. [47]
    Carty M, Goodbody R, Schroder M, Stack J, Moynagh PN, Bowie AG. The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nat Immunol 2006, 7: 1074–1081.PubMedCrossRefGoogle Scholar
  48. [48]
    Chuang CF, Bargmann CI. A Toll-interl eukin 1 repeat protein at the synapse specifies asymmetric odorant receptor expression via ASK1 MAPKKK signaling. Genes Dev 2005, 19: 270–281.PubMedCentralPubMedCrossRefGoogle Scholar
  49. [49]
    Chang C, Hsieh YW, Lesch BJ, Bargmann CI, Chuang CF. Microtubule-based localization of a synaptic calcium-signaling complex is required for left-right neuronal asymmetry in C. elegans. Development 2011, 138: 3509–3518.PubMedCentralPubMedCrossRefGoogle Scholar
  50. [50]
    Murata H, Sakaguchi M, Kataoka K, Huh N H. SARM1 and TRAF6 bind to and stabilize PINK1 on depolarized mitochondria. Mol Biol Cell 2013, 24: 2772–2784.PubMedCentralPubMedCrossRefGoogle Scholar
  51. [51]
    Mukherjee P, Woods TA, Moore RA, Peterson KE. Activation of the innate signaling molecule MAVS by bunyavirus infection upregulates the adaptor protein SARM1, leading to neuronal death. Immunity 2013, 38: 705–716.PubMedCrossRefGoogle Scholar
  52. [52]
    Lin Y-L, Lei Y-T, Hong C-J, Hsueh YP. Syn decan-2 induces filopodia formation via the neurofibromin-PKA-Ena/VASP pathway. J Cell Biol 2007, 177: 829–841.PubMedCentralPubMedCrossRefGoogle Scholar
  53. [53]
    Hsueh YP, Roberts AM, Volta M, Sheng M, Roberts RG. Bipartite interaction between neurofibromatosis type I protein (neurofibromin) and syndecan transmembrane heparan sulfate proteoglycans. J Neurosci 2001, 21: 3764–3770.PubMedGoogle Scholar
  54. [54]
    Chao HW, Hong CJ, Huang TN, Lin YL, Hsueh Y P. SUMOylation of the MAGUK protein CASK regulates dendritic spinogenesis. J Cell Biol 2008, 182: 141–155.PubMedCentralPubMedCrossRefGoogle Scholar
  55. [55]
    Osterloh JM, Yang J, Rooney TM, Fox AN, Adalbert R, Powell EH, et al. dSarm/Sarm1 is required for activation of an injuryinduced axon death pathway. Science 2012, 337: 481–484.PubMedCrossRefGoogle Scholar
  56. [56]
    Gerdts J, Summers DW, Sasaki Y, DiAntonio A, Milbrandt J. Sarm1-mediated axon degeneration requires both SAM and TIR interactions. J Neurosci 2013, 33: 13569–13580.PubMedCentralPubMedCrossRefGoogle Scholar
  57. [57]
    Lin CW, Hsueh YP. Sarm1, a neuronal inflammato ry regulator, controls social interaction, associative memory and cognitive flexibility in mice. Brain Behav Immun 2014, 37: 142–151.PubMedCrossRefGoogle Scholar
  58. [58]
    Lin CW, Chen CY, Cheng SJ, HU HT, Hsueh YP. Sarm1 deficiency impairs synaptic function and leads to behavioral deficits, which can be ameliorated by an mGluR allosteric modulator. Front Cell Neurosci 2014, 8: 87.PubMedCentralPubMedGoogle Scholar
  59. [59]
    Pardo C, Azhagiri A, Lawler C, Zea-Vera A. Expr ession Profiling of TLR Signaling Pathway Genes in Brain Tissue from Patients with Autism. International Meeting for Autism Research 2009, 131.05.Google Scholar
  60. [60]
    Ascano M, Jr., Mukherjee N, Bandaru P, Miller JB, Nusbaum JD, Corcoran DL, et al. FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature 2012, 492: 382–386.PubMedCentralPubMedCrossRefGoogle Scholar
  61. [61]
    Lathia JD, Okun E, Tang SC, Griffioen K, Cheng A, Mughal MR, et al. Toll-like receptor 3 is a negative regulator of embryonic neural progenitor cell proliferation. J Neurosci 2008, 28: 13978–13984.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Institute of Molecular BiologyAcademia SinicaTaipeiTaiwan
  2. 2.Graduate Institute of Life SciencesNational Defense Medical CenterTaipeiTaiwan

Personalised recommendations