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Toll-like receptor 4 (TLR4) influences the glial reaction in the spinal cord and the neural response to injury following peripheral nerve crush.
Brain Res Bull. 2020 02; 155:67-80.BR

Abstract

After peripheral axotomy, there is a selective retraction of synaptic terminals in contact with injured motoneurons. This process, which actively involves glial cells, is influenced by the expression of immune-related molecules. Since toll-like receptors (TLRs) are upregulated by astrocytes and microglia following lesions, they might be involved in synaptic plasticity processes. Therefore, we administered lipopolysaccharide (LPS) to enhance TLR4 expression in mice and studied retrograde changes in the spinal cord ventral horn following sciatic nerve crush. To this end, adult C57BL/6J male mice were subjected to unilateral sciatic nerve crush at the mid-thigh level and, after a survival time of seven and forty days (acute and chronic phases, respectively), the spinal cords were paraformaldehyde-fixed and dissected out for immunolabeling for synaptophysin, glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1). The results show that TLR4 upregulation leads to synaptophysin downregulation close to spinal motoneuron cell bodies, indicating increased synaptic elimination. LPS exposure also further increases astrogliosis and microglial reactions in the both ventral and dorsal horns, especially ipsilateral to nerve axotomy, compared to those in untreated mice. Notably, LPS administration to TLR4-/- mice produces results similar to those observed in untreated wild-type counterparts, reinforcing the role of this receptor in the glial response to injury. Therefore, our results suggest that the overexpression of the TLR4 receptor results in augmented astrogliosis/microglial reactions and the excessive loss of synapses postinjury, which may, in turn, affect the motoneuronal regenerative response and functionality. Additionally, treatment with LPS increases the expression of β2-microglobulin, a subcomponent of MHC I. Importantly, the absence of TLR4 results in imbalanced axonal regeneration, inducing subsequent improvements and setbacks. In conclusion, our results show the involvement of TLR4 in the process of synaptic remodeling, indicating a new target for future research aimed at developing therapies for CNS and PNS repair.

Authors+Show Affiliations

Department of Structural and Functional Biology, University of Campinas (UNICAMP), PO Box 6109, Campinas 13083-970, São Paulo, Brazil. Electronic address: paty.ribeiro2@hotmail.com.Department of Structural and Functional Biology, University of Campinas (UNICAMP), PO Box 6109, Campinas 13083-970, São Paulo, Brazil. Electronic address: mateusvidigal@hotmail.com.Department of Structural and Functional Biology, University of Campinas (UNICAMP), PO Box 6109, Campinas 13083-970, São Paulo, Brazil. Electronic address: Matheus_perez13@hotmail.com.Department of Structural and Functional Biology, University of Campinas (UNICAMP), PO Box 6109, Campinas 13083-970, São Paulo, Brazil. Electronic address: lucartarozzi@gmail.com.Department of Structural and Functional Biology, University of Campinas (UNICAMP), PO Box 6109, Campinas 13083-970, São Paulo, Brazil. Electronic address: aline.spejo@gmail.com.Department of Structural and Functional Biology, University of Campinas (UNICAMP), PO Box 6109, Campinas 13083-970, São Paulo, Brazil. Electronic address: gabrielachiarotto@gmail.com.Jundiaí Medical School, Jundiaí, São Paulo, Brazil. Electronic address: taizea@gmail.com.Department of Structural and Functional Biology, University of Campinas (UNICAMP), PO Box 6109, Campinas 13083-970, São Paulo, Brazil. Electronic address: alroliv@unicamp.br.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31756421

Citation

Ribeiro, Patrícia, et al. "Toll-like Receptor 4 (TLR4) Influences the Glial Reaction in the Spinal Cord and the Neural Response to Injury Following Peripheral Nerve Crush." Brain Research Bulletin, vol. 155, 2020, pp. 67-80.
Ribeiro P, Castro MV, Perez M, et al. Toll-like receptor 4 (TLR4) influences the glial reaction in the spinal cord and the neural response to injury following peripheral nerve crush. Brain Res Bull. 2020;155:67-80.
Ribeiro, P., Castro, M. V., Perez, M., Cartarozzi, L. P., Spejo, A. B., Chiarotto, G. B., Augusto, T. M., & Oliveira, A. L. R. (2020). Toll-like receptor 4 (TLR4) influences the glial reaction in the spinal cord and the neural response to injury following peripheral nerve crush. Brain Research Bulletin, 155, 67-80. https://doi.org/10.1016/j.brainresbull.2019.11.008
Ribeiro P, et al. Toll-like Receptor 4 (TLR4) Influences the Glial Reaction in the Spinal Cord and the Neural Response to Injury Following Peripheral Nerve Crush. Brain Res Bull. 2020;155:67-80. PubMed PMID: 31756421.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Toll-like receptor 4 (TLR4) influences the glial reaction in the spinal cord and the neural response to injury following peripheral nerve crush. AU - Ribeiro,Patrícia, AU - Castro,Mateus V, AU - Perez,Matheus, AU - Cartarozzi,Luciana P, AU - Spejo,Aline B, AU - Chiarotto,Gabriela B, AU - Augusto,Taize M, AU - Oliveira,Alexandre L R, Y1 - 2019/11/19/ PY - 2019/07/14/received PY - 2019/10/05/revised PY - 2019/11/15/accepted PY - 2019/11/23/pubmed PY - 2019/11/23/medline PY - 2019/11/23/entrez KW - Axotomy KW - MHC I KW - Plasticity KW - Sciatic nerve KW - Toll-like receptor 4 SP - 67 EP - 80 JF - Brain research bulletin JO - Brain Res. Bull. VL - 155 N2 - After peripheral axotomy, there is a selective retraction of synaptic terminals in contact with injured motoneurons. This process, which actively involves glial cells, is influenced by the expression of immune-related molecules. Since toll-like receptors (TLRs) are upregulated by astrocytes and microglia following lesions, they might be involved in synaptic plasticity processes. Therefore, we administered lipopolysaccharide (LPS) to enhance TLR4 expression in mice and studied retrograde changes in the spinal cord ventral horn following sciatic nerve crush. To this end, adult C57BL/6J male mice were subjected to unilateral sciatic nerve crush at the mid-thigh level and, after a survival time of seven and forty days (acute and chronic phases, respectively), the spinal cords were paraformaldehyde-fixed and dissected out for immunolabeling for synaptophysin, glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1). The results show that TLR4 upregulation leads to synaptophysin downregulation close to spinal motoneuron cell bodies, indicating increased synaptic elimination. LPS exposure also further increases astrogliosis and microglial reactions in the both ventral and dorsal horns, especially ipsilateral to nerve axotomy, compared to those in untreated mice. Notably, LPS administration to TLR4-/- mice produces results similar to those observed in untreated wild-type counterparts, reinforcing the role of this receptor in the glial response to injury. Therefore, our results suggest that the overexpression of the TLR4 receptor results in augmented astrogliosis/microglial reactions and the excessive loss of synapses postinjury, which may, in turn, affect the motoneuronal regenerative response and functionality. Additionally, treatment with LPS increases the expression of β2-microglobulin, a subcomponent of MHC I. Importantly, the absence of TLR4 results in imbalanced axonal regeneration, inducing subsequent improvements and setbacks. In conclusion, our results show the involvement of TLR4 in the process of synaptic remodeling, indicating a new target for future research aimed at developing therapies for CNS and PNS repair. SN - 1873-2747 UR - https://www.unboundmedicine.com/medline/citation/31756421/Toll_like_receptor_4__TLR4__influences_the_glial_reaction_in_the_spinal_cord_and_the_neural_response_to_injury_following_peripheral_nerve_crush_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0361-9230(19)30553-2 DB - PRIME DP - Unbound Medicine ER -
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