Motoneuronal inflammasome activation triggers excessive neuroinflammation and impedes regeneration after sciatic nerve injury.

Humans Inflammasomes / metabolism Motor Neurons / metabolism NLR Family, Pyrin Domain-Containing 3 Protein / metabolism Neuroinflammatory Diseases Peripheral Nerve Injuries Sciatic Nerve / injuries

Axotomy Extracellular ATP IL-1β Inflammasome Motoneuron NLRP3 Regeneration Reinnervation Sciatic nerve injury

Journal

Journal of neuroinflammation

ISSN: 1742-2094

Titre abrégé: J Neuroinflammation

Pays: England

ID NLM: 101222974

Informations de publication

Date de publication:
19 Mar 2022

Historique:

received: 07 09 2021

accepted: 01 03 2022

entrez: 20 3 2022

pubmed: 21 3 2022

medline: 8 4 2022

Statut: epublish

Résumé

Peripheral nerve injuries are accompanied by inflammatory reactions, over-activation of which may hinder recovery. Among pro-inflammatory pathways, inflammasomes are one of the most potent, leading to release of active IL-1β. Our aim was to understand how inflammasomes participate in central inflammatory reactions accompanying peripheral nerve injury. After axotomy of the sciatic nerve, priming and activation of the NLRP3 inflammasome was examined in cells of the spinal cord. Regeneration of the nerve was evaluated after coaptation using sciatic functional index measurements and retrograde tracing. In the first 3 days after the injury, elements of the NLRP3 inflammasome were markedly upregulated in the L4-L5 segments of the spinal cord, followed by assembly of the inflammasome and secretion of active IL-1β. Although glial cells are traditionally viewed as initiators of neuroinflammation, in this acute phase of inflammation, inflammasome activation was found exclusively in affected motoneurons of the ventral horn in our model. This process was significantly inhibited by 5-BDBD, a P2X4 receptor inhibitor and MCC950, a potent NLRP3 inhibitor. Although at later time points the NLRP3 protein was upregulated in microglia too, no signs of inflammasome activation were detected in these cells. Inhibition of inflammasome activation in motoneurons in the first days after nerve injury hindered development of microgliosis in the spinal cord. Moreover, P2X4 or inflammasome inhibition in the acute phase significantly enhanced nerve regeneration on both the morphological and the functional levels. Our results indicate that the central reaction initiated by sciatic nerve injury starts with inflammasome activation in motoneurons of the ventral horn, which triggers a complex inflammatory reaction and activation of microglia. Inhibition of neuronal inflammasome activation not only leads to a significant reduction of microgliosis, but has a beneficial effect on the recovery as well.

Sections du résumé

BACKGROUND BACKGROUND

METHODS METHODS

After axotomy of the sciatic nerve, priming and activation of the NLRP3 inflammasome was examined in cells of the spinal cord. Regeneration of the nerve was evaluated after coaptation using sciatic functional index measurements and retrograde tracing.

RESULTS RESULTS

In the first 3 days after the injury, elements of the NLRP3 inflammasome were markedly upregulated in the L4-L5 segments of the spinal cord, followed by assembly of the inflammasome and secretion of active IL-1β. Although glial cells are traditionally viewed as initiators of neuroinflammation, in this acute phase of inflammation, inflammasome activation was found exclusively in affected motoneurons of the ventral horn in our model. This process was significantly inhibited by 5-BDBD, a P2X4 receptor inhibitor and MCC950, a potent NLRP3 inhibitor. Although at later time points the NLRP3 protein was upregulated in microglia too, no signs of inflammasome activation were detected in these cells. Inhibition of inflammasome activation in motoneurons in the first days after nerve injury hindered development of microgliosis in the spinal cord. Moreover, P2X4 or inflammasome inhibition in the acute phase significantly enhanced nerve regeneration on both the morphological and the functional levels.

CONCLUSIONS CONCLUSIONS

Our results indicate that the central reaction initiated by sciatic nerve injury starts with inflammasome activation in motoneurons of the ventral horn, which triggers a complex inflammatory reaction and activation of microglia. Inhibition of neuronal inflammasome activation not only leads to a significant reduction of microgliosis, but has a beneficial effect on the recovery as well.

Identifiants

DOI: 10.1186/s12974-022-02427-9 PMID: 35305649 PMC: PMC8934511

pubmed: 35305649

doi: 10.1186/s12974-022-02427-9

pii: 10.1186/s12974-022-02427-9

pmc: PMC8934511

doi:

Substances chimiques

Inflammasomes 0

NLR Family, Pyrin Domain-Containing 3 Protein 0

Types de publication

Journal Article

Langues

eng