Top

Journal of Neuroinflammation

Published in:

Open Access 01-12-2012 | Research

Opposing effects of Toll-like receptors 2 and 4 on synaptic stability in the spinal cord after peripheral nerve injury

Authors: Camila Marques Freria, Licio Augusto Velloso, Alexandre LR Oliveira

Published in: Journal of Neuroinflammation | Issue 1/2012

Abstract

Background

Glial cells are involved in the synaptic elimination process that follows neuronal lesions, and are also responsible for mediating the interaction between the nervous and immune systems. Neurons and glial cells express Toll-like receptors (TLRs), which may affect the plasticity of the central nervous system (CNS). Because TLRs might also have non-immune functions in spinal-cord injury (SCI), we aimed to investigate the influence of TLR2 and TLR4 on synaptic plasticity and glial reactivity after peripheral nerve axotomy.

Methods

The lumbar spinal cords of C3H/HePas wild-type (WT) mice, C3H/HeJ TLR4-mutant mice, C57BL/6J WT mice, and C57BL/6J TLR2 knockout (KO) mice were studied after unilateral sciatic nerve transection. The mice were killed via intracardiac perfusion, and the spinal cord was processed for immunohistochemistry, transmission electron microscopy (TEM), western blotting, cell culture, and reverse transcriptase PCR. Primary cultures of astrocytes from newborn mice were established to study the astrocyte response in the absence of TLR2 and the deficiency of TLR4 expression.

Results

The results showed that TLR4 and TLR2 expression in the CNS may have opposite effects on the stability of presynaptic terminals in the spinal cord. First, TLR4 contributed to synaptic preservation of terminals in apposition to lesioned motor neurons after peripheral injury, regardless of major histocompatibility complex class I (MHC I) expression. In addition, in the presence of TLR4, there was upregulation of glial cell-derived neurotrophic factor and downregulation of interleukin-6, but no morphological differences in glial reactivity were seen. By contrast, TLR2 expression led to greater synaptic loss, correlating with increased astrogliosis and upregulation of pro-inflammatory interleukins. Moreover, the absence of TLR2 resulted in the upregulation of neurotrophic factors and MHC I expression.

Conclusion

TLR4 and TLR2 in the CNS may have opposite effects on the stability of presynaptic terminals in the spinal cord and in astroglial reactions, indicating possible roles for these proteins in neuronal and glial responses to injury.

Available only for authorised users

Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CJ: Functional requirement for class I MHC in CNS development and plasticity. Science 2000,290(5499):2155–2159.CrossRefPubMedPubMedCentral

Oliveira AL, Thams S, Lidman O, Piehl F, Hökfelt T, Kärre K, Lindå H, Culheim S: A role for MHC class I molecules in synaptic plasticity and regeneration of neurons after axotomy. Proc Natl Acad Sci 2004, 101:17843–17848.CrossRefPubMedPubMedCentral

Berg A, Zelano J, Stephan A, Thams S, Barres BA, Pekny M, Pekna M, Cullheim S: Reduced removal of synaptic terminals from axotomized spinal motoneurons in the absence of complement C3. Exp Neurol 2012,237(1):8–17.CrossRefPubMed

Fourgeaud L, Boulanger LM: Synapse remodeling, compliments of the complement system. Cell 2007,131(6):1034–1036.CrossRefPubMed

Aldskogius H, Liu L, Svensson M: Glial responses to synaptic damage and plasticity. J Neurosci Res 1999,58(1):33–41.CrossRefPubMed

Emirandetti A, Zanon RG, Sabha JR, Oliveira ALR: Astrocyte reactivity influences the number of presynaptic terminals apposed to spinal motoneurons after axotomy. Brain Res 2006, 1095:35–42.CrossRefPubMed

Lehnardt S, Lachance C, Patrizi S, Lefebvre S, Follett PL, Jensen FE, Rosenberg PA, Volpe JJ, Vartanian T: The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci 2002,22(7):2478–2486.PubMed

Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, Vartanian T: Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A 2003,100(14):8514–8519.CrossRefPubMedPubMedCentral

Lehnardt S: Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia 2010,58(3):253–263.PubMed

10.

Jack CS, Arbour N, Manusow J, Montgrain V, Blain M, McCrea E, Shapiro A, Antel JP: TLR signaling tailors innate immune responses in human microglia and astrocytes. J Immunol 2005, 22:4320–4330.CrossRef

11.

Henn A, Kirner S, Leist M: TLR2 hypersensitivity of astrocytes as functional consequence of previous inflammatory episodes. J Immunol 2011,186(5):3237–3247.CrossRefPubMed

12.

Goethals S, Ydens E, Timmerman V, Janssens S: Toll-like receptor expression in the peripheral nerve. Glia 2010,58(14):1701–1709.CrossRefPubMed

13.

Tang SC, Arumugam TV, Xu X, Cheng A, Mughal MR, Jo DG, Lathia JD, Siler DA, Chigurupati S, Ouyang X, Magnus T, Camandola S, Mattson MP: Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci USA 2007,104(34):13798–13803.CrossRefPubMedPubMedCentral

14.

Bowman CC, Rasley A, Tranguch SL, Marriott I: Cultured astrocytes express toll-like receptors for bacterial products. Glia 2003,43(3):281–291.CrossRefPubMed

15.

Olson JK, Miller SD: Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 2004,173(6):3916–3924.CrossRefPubMed

16.

Phulwani NK, Esen N, Syed MM, Kielian T: TLR2 expression in astrocytes is induced by TNF-alpha- and NF-kappa B-dependent pathways. J Immunol 2008,181(6):3841–3849.CrossRefPubMedPubMedCentral

17.

Lindå H, Shupliakov O, Örnung G, Ottersen OP, Storm-Mathisen J, Risling M, Cullheim S: Ultrastructural evidence for a preferential elimination of glutamate-immunoreactive synaptic terminals from spinal motoneurons after intramedullary axotomy. J Comp Neurol 2000, 425:10–23.CrossRefPubMed

18.

Cullheim S, Thams S: The microglial networks of brain and their role in neural network plasticity after lesion. Brain Res Rev 2007, 55:89–96.CrossRefPubMed

19.

Schiefer J, Kampe K, Dodt HU, Zieglgänsberger W, Kreutzberg GW: Microglial motility in the rat facial nucleus following peripheral axotomy. J Neurocytol 1999,28(6):439–453.CrossRefPubMed

20.

Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B: Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998,282(5396):2085–2088.CrossRefPubMed

21.

Conradi S: On motoneuron synaptology in adult cats. Acta Physiol Scand 1969, 332:1–57.

22.

McCarthy KD, Vellis J: Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 1980, 85:890–902.CrossRefPubMed

23.

Boulanger LM, Huh GS, Shatz CJ: Neuronal plasticity and cellular immunity: shared molecular mechanisms. Curr Opin Neurobiol 2001,11(5):568–578.CrossRefPubMed

24.

Ma Y, Li J, Chiu I, Wang Y, Sloane JA, Lü J, Kosaras B, Sidman RL, Volpe JJ, Vartanian T: Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis. J Cell Biol 2006,175(2):209–215.CrossRefPubMedPubMedCentral

25.

Li Y, Li H, Zhang Y, Sun X, Hanley GA, LeSage G, Zhang Y, Sun S, Peng Y, Yin D: Toll-like receptor 2 is required for opioids-induced neuronal apoptosis. Biochem Biophys Res Commun 2010,391(1):426–430.CrossRefPubMed

26.

Rolls A, Shechter R, London A, Ziv Y, Ronen A, Levy R, Schwartz M: Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol 2007,9(9):1081–1088.CrossRefPubMed

27.

Wainwright DA, Xin J, Mesnard NA, Sanders VM, Jones KJ: Toll-like receptor 2 and facial motoneuron survival after facial nerve axotomy. Neurosci Lett 2010,471(1):10–14.CrossRefPubMedPubMedCentral

28.

Ziegler G, Harhausen D, Schepers C, Hoffmann O, Röhr C, Prinz V, König J, Lehrach H, Nietfeld W, Trendelenburg G: TLR2 has a detrimental role in mouse transient focal cerebral ischemia. Biochem Biophys Res Commun 2007,359(3):574–579.CrossRefPubMed

29.

Okun E, Griffioen KJ, Mattson MP: Toll-like receptor signaling in neural plasticity and disease. TINS 2011,34(5):269–281.PubMedPubMedCentral

30.

Kigerl KA, Lai W, Rivest S, Hart RP, Satoskar AR, Popovich PG: Toll-like receptor (TLR)-2 and TLR-4 regulate inflammation, gliosis, and myelin sparing after spinal cord injury. J Neurochem 2007,102(1):37–50.CrossRefPubMed

31.

Boivin A, Pineau I, Barrette B, Filali M, Vallieres N, Rivest S, Lacroix S: Toll like receptor signaling is critical for wallerian degeneration and functional recovery after peripheral nerve injury. J Neurosci 2007, 27:12565–12576.CrossRefPubMed

32.

Benveniste EN, Sparacio SM, Norris JG, Grenett HE, Fuller GM: Induction and regulation of interleukin-6 gene expression in rat astrocytes. J Neuroimmunol 1990,30(2–3):201–212.CrossRefPubMed

33.

Lee SC, Liu W, Dickson DW, Brosnan CF, Berman JW: Cytokine production by human fetal microglia and astrocytes. Differential induction by lipopolysaccharide and IL-1 beta. J Immunol 1993,150(7):2659–2667.PubMed

34.

John GR, Lee SC, Song X, Rivieccio M, Brosnan CF: IL-1-regulated responses in astrocytes: relevance to injury and recovery. Glia 2005,49(2):161–176.CrossRefPubMed

35.

Herx LM, Rivest S, Yong VW: Central nervous system-initiated inflammation and neurotrophism in trauma: IL-1 beta is required for the production of ciliary neurotrophic factor. J Immunol 2000,165(4):2232–2239.CrossRefPubMed

36.

Pinteaux E, Rothwell NJ, Boutin H: Neuroprotective actions of endogenous interleukin-1 receptor antagonist (IL-1ra) are mediated by glia. Glia 2006,53(5):551–556.CrossRefPubMed

37.

Hailer NP, Vogt C, Korf HW, Dehghani F: Interleukin-1beta exacerbates and interleukin-1 receptor antagonist attenuates neuronal injury and microglial activation after excitotoxic damage in organotypic hippocampal slice cultures. Eur J Neurosci 2005,21(9):2347–2360.CrossRefPubMed

38.

Joseph MS, Bilousova T, Zdunowski S, Wu ZP, Middleton B, Boudzinskaia M, Wong B, Ali N, Zhong H, Yong J, Washburn L, Escande-Beillard N, Dang H, Edgerton VR, Tillakaratne NJ, Kaufman DL: Transgenic mice with enhanced neuronal major histocompatibility complex class I expression recover locomotor function better after spinal cord injury. J Neurosci 2011,89(3):365–372.

39.

Kim D, Kim MA, Cho IH, Kim MS, Lee S, Jo EK, Choi SY, Park K, Kim JS, Akira S, Na HS, Oh SB, Lee SJ: A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity. J Biol Chem 2007,282(20):14975–14983.CrossRefPubMed

40.

Rao JS, Kellom M, Kim HW, Rapoport SI, Reese EA: Neuroinflammation and synaptic loss. Neurochem Res 2012,37(5):903–910.CrossRefPubMedPubMedCentral

41.

Boyd JG, Gordon T: Glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor sustain the axonal regeneration of chronically axotomized motoneurons in vivo. Exp Neurol 2003, 183:610–619.CrossRefPubMed

42.

Black IB: Trophic regulation of synaptic plasticity. J Neurobiol 1999,41(1):108–118.CrossRefPubMed

43.

Novikov LN, Novikova LN, Holmberg P, Kellerth J: Exogenous brain-derived neurotrophic factor regulates the synaptic composition of axonally lesioned and normal adult rat motoneurons. Neuroscience 2000,100(1):171–181.CrossRefPubMed

44.

Naveilhan P, ElShamy WM, Ernfors P: Differential regulation of mRNAs for GDNF and its receptors Ret and GDNFR alpha after sciatic nerve lesion in the mouse. Eur J Neurosci 1997,9(7):1450–1460.CrossRefPubMed

Title: Opposing effects of Toll-like receptors 2 and 4 on synaptic stability in the spinal cord after peripheral nerve injury
Authors: Camila Marques Freria
Licio Augusto Velloso
Alexandre LR Oliveira
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/1742-2094-9-240

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Opposing effects of Toll-like receptors 2 and 4 on synaptic stability in the spinal cord after peripheral nerve injury

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2012

Prevention of methamphetamine-induced microglial cell death by TNF-α and IL-6 through activation of the JAK-STAT pathway

Upregulation of mesencephalic astrocyte-derived neurotrophic factor in glial cells is associated with ischemia-induced glial activation

P2X7 signaling promotes microsphere embolism-triggered microglia activation by maintaining elevation of Fas ligand

Immunological characterization and transcription profiling of peripheral blood (PB) monocytes in children with autism spectrum disorders (ASD) and specific polysaccharide antibody deficiency (SPAD): case study

Effects of anti-inflammatory vagus nerve stimulation on the cerebral microcirculation in endotoxinemic rats

Proteolytic activation of proapoptotic kinase protein kinase Cδ by tumor necrosis factor α death receptor signaling in dopaminergic neurons during neuroinflammation