Impairment of toll-like receptors 2 and 4 leads to compensatory mechanisms after sciatic nerve axotomy

Autor(es)

Freria, C. M. ^[1] ; Bernardes, D. ^[1] ; Almeida, G. L. ^[1] ; Simoes, G. F. ^[1] ; Barbosa, G. O. ^[1] ; Oliveira, A. L. R. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Inst Biol, Dept Struct & Funct Biol, Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF NEUROINFLAMMATION; v. 13, MAY 24 2016.
• Citações Web of Science: 13

Resumo

Background: Peripheral nerve injury results in retrograde cell body-related changes in the spinal motoneurons that will contribute to the regenerative response of their axons. Successful functional recovery also depends on molecular events mediated by innate immune response during Wallerian degeneration in the nerve microenvironment. A previous study in our lab demonstrated that TLR 2 and 4 develop opposite effects on synaptic stability in the spinal cord after peripheral nerve injury. Therefore, we suggested that the better preservation of spinal cord microenvironment would positively influence distal axonal regrowth. In this context, the present work aimed to investigate the influence of TLR2 and TLR4 on regeneration and functional recovery after peripheral nerve injury. Methods: Eighty-eight mice were anesthetized and subjected to unilateral sciatic nerve crush (C3H/HeJ, n = 22, C3H/HePas, n = 22; C57Bl6/J, n = 22 and TLR2(-/-), n = 22). After the appropriate survival times (3, 7, 14 days, and 5 weeks), all mice were killed and the sciatic nerves and tibialis cranialis muscles were processed for immunohistochemistry and transmission electron microscopy (TEM). Gait analysis, after sciatic nerve crushing, was performed in another set of mice (minimum of n = 8 per group), by using the walking track test (CatWalk system). Results: TLR4 mutant mice presented greater functional recovery as well as an enhanced p75(NTR) and neurofilament protein expression as compared to the wild-type strain. Moreover, the better functional recovery in mutant mice was correlated to a greater number of nerve terminal sprouts. Knockout mice for TLR2 exhibited 30 % greater number of degenerated axons in the distal stump of the sciatic nerve and a decreased p75NTR and neurofilament protein expression compared to the wild type. However, the absence of TLR2 receptor did not influence the overall functional recovery. End-point equivalent functional recovery in transgenic mice may be a result of enhanced axonal diameter found at 2 weeks after lesion. Conclusions: Altogether, the present results indicate that the lack of TLR2 or the absence of functional TLR4 does affect the nerve regeneration process; however, such changes are minimized through different compensatory mechanisms, resulting in similar motor function recovery, as compared to wild-type mice. These findings contribute to the concept that innate immune-related molecules influence peripheral nerve regeneration by concurrently participating in processes taking place both at the CNS and PNS. (AU)

• Processo FAPESP: 10/07476-2 - Influência do receptor toll like 2 na regeneração nervosa periférica após esmagamento do nervo isquiático
• Beneficiário: Gabriela Almeida Leite
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 09/50307-0 - Influência dos receptores toll like 2 e toll like 4 na reatividade glial e plasticidade sináptica de motoneurônios medulares após lesão periférica
• Beneficiário: Camila Marques de Freria
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 10/17688-7 - Influência dos receptores Toll like 2 e 4 na reatividade glial e plasticidade sináptica de motoneurônios medulares após axotomia periférica
• Beneficiário: Alexandre Leite Rodrigues de Oliveira
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/04665-2 - Estudo sobre a eficácia neuroprotetora dos imunomoduladores em camundongos com encefalomielite autoimune experimental (EAE) previamente submetidos a protocolo de pré-condicionamento pelo exercício físico
• Beneficiário: Danielle Bernardes
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado