Inhibition of leucine-rich repeats and calponin homology domain containing 1 accelerates microglia-mediated neuroinflammation in a rat traumatic spinal cord injury model.

Wen-Kai Chen, Lin-Juan Feng, Qiao-Dan Liu, Qing-Feng Ke, Pei-Ya Cai, Pei-Ru Zhang, Li-Quan Cai, Nian-Lai Huang, Wen-Ping Lin

Journal of neuroinflammation 2020 Jul 06

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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. 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. 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. 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.

Citation

Wen-Kai Chen, Lin-Juan Feng, Qiao-Dan Liu, Qing-Feng Ke, Pei-Ya Cai, Pei-Ru Zhang, Li-Quan Cai, Nian-Lai Huang, Wen-Ping Lin. Inhibition of leucine-rich repeats and calponin homology domain containing 1 accelerates microglia-mediated neuroinflammation in a rat traumatic spinal cord injury model. Journal of neuroinflammation. 2020 Jul 06;17(1):202