Abstract
BackgroundSpinal 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.MethodsTo 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.ResultsWe 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.ConclusionOur 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.
Highlights
Spinal cord injury (SCI) triggers the primary mechanical injury and secondary inflammation-mediated injury
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
LRCH1 is downregulated in post-SCI microglia To determine LRCH1 expression in microglia, we first enriched leukocytes from the spinal cords of sham-operated rats and SCI rats (Fig. 1a)
Summary
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. The mechanical trauma of the spinal cord tissue initiates the primary injury, while the secondary neuroinflammatory reactions, which mediate additional and extensive neurological injury, take place following the primary injury. Microglia play a pivotal role in the post-SCI secondary injury. Previous studies showed that microglia clear damaged and degenerate tissues [6], while depletion of microglia after SCI reduces neuronal and oligodendrocyte survival and impairs locomotor recovery [7]. It seems the overall effect of microglia is beneficial to spinal cord recovery. Carefully tuning the microglia function to minimize their detrimental effect and boast their neuroprotective effect is vital to promote neurological recovery
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