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Inhibition of leucine-rich repeats and calponin homology domain containing 1 accelerates microglia-mediated neuroinflammation in a rat traumatic spinal cord injury model.
- Source :
-
Journal of neuroinflammation [J Neuroinflammation] 2020 Jul 06; Vol. 17 (1), pp. 202. Date of Electronic Publication: 2020 Jul 06. - Publication Year :
- 2020
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Abstract
- Background: Spinal cord injury (SCI) triggers the primary mechanical injury and secondary inflammation-mediated injury. Neuroinflammation-mediated insult causes secondary and extensive neurological damage after SCI. Microglia play a pivotal role in the initiation and progression of post-SCI neuroinflammation.<br />Methods: To elucidate the significance of LRCH1 to microglial functions, we applied lentivirus-induced LRCH1 knockdown in primary microglia culture and tested the role of LRCH1 in microglia-mediated inflammatory reaction both in vitro and in a rat SCI model.<br />Results: We found that LRCH1 was downregulated in microglia after traumatic SCI. LRCH1 knockdown increased the production of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6 after in vitro priming with lipopolysaccharide and adenosine triphosphate. Furthermore, LRCH1 knockdown promoted the priming-induced microglial polarization towards the pro-inflammatory inducible nitric oxide synthase (iNOS)-expressing microglia. LRCH1 knockdown also enhanced microglia-mediated N27 neuron death after priming. Further analysis revealed that LRCH1 knockdown increased priming-induced activation of p38 mitogen-activated protein kinase (MAPK) and Erk1/2 signaling, which are crucial to the inflammatory response of microglia. When LRCH1-knockdown microglia were adoptively injected into rat spinal cords, they enhanced post-SCI production of pro-inflammatory cytokines, increased SCI-induced recruitment of leukocytes, aggravated SCI-induced tissue damage and neuronal death, and worsened the locomotor function.<br />Conclusion: Our study reveals for the first time that LRCH1 serves as a negative regulator of microglia-mediated neuroinflammation after SCI and provides clues for developing novel therapeutic approaches against SCI.
- Subjects :
- Animals
Cells, Cultured
Inflammation chemically induced
Inflammation metabolism
Inflammation pathology
Lipopolysaccharides toxicity
Male
Microglia drug effects
Microglia pathology
Rats
Rats, Sprague-Dawley
Spinal Cord Injuries pathology
Inflammation Mediators metabolism
Microfilament Proteins antagonists & inhibitors
Microfilament Proteins metabolism
Microglia metabolism
Spinal Cord Injuries metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1742-2094
- Volume :
- 17
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of neuroinflammation
- Publication Type :
- Academic Journal
- Accession number :
- 32631435
- Full Text :
- https://doi.org/10.1186/s12974-020-01884-4