Excessive inflammation post-traumatic spinal cord injury(SCI)induces microglial activation,which leads to prolonged neurological dysfunction.However,the mechanism underlying microglial activation-induced neuroinflamma...Excessive inflammation post-traumatic spinal cord injury(SCI)induces microglial activation,which leads to prolonged neurological dysfunction.However,the mechanism underlying microglial activation-induced neuroinflammation remains poorly understood.Ruxolitinib(RUX),a selective inhibitor of JAK1/2,was recently reported to inhibit inflammatory storms caused by SARS-CoV-2 in the lung.However,its role in disrupting inflammation post-SCI has not been confirmed.In this study,microglia were treated with RUX for 24 hours and then activated with interferon-γfor 6 hours.The results showed that interferon-γ-induced phosphorylation of JAK and STAT in microglia was inhibited,and the mRNA expression levels of pro-inflammatory cytokines tumor necrosis factor-α,interleukin-1β,interleukin-6,and cell proliferation marker Ki67 were reduced.In further in vivo experiments,a mouse model of spinal cord injury was treated intragastrically with RUX for 3 successive days,and the findings suggest that RUX can inhibit microglial proliferation by inhibiting the interferon-γ/JAK/STAT pathway.Moreover,microglia treated with RUX centripetally migrated toward injured foci,remaining limited and compacted within the glial scar,which resulted in axon preservation and less demyelination.Moreover,the protein expression levels of tumor necrosis factor-α,interleukin-1β,and interleukin-6 were reduced.The neuromotor function of SCI mice also recovered.These findings suggest that RUX can inhibit neuroinflammation through inhibiting the interferon-γ/JAK/STAT pathway,thereby reducing secondary injury after SCI and producing neuroprotective effects.展开更多
基金supported by the National Natural Science Foundation of China,Nos.81871773(to XJC),81672152(to XJC),81802149(to LY)Primary Research and Development Plan of Jiangsu Province of China,No.BE2018132(to XJC)Scientific Research Project of Health Commission of Jiangsu Province of China,No.LGY2020068(to HJL).
文摘Excessive inflammation post-traumatic spinal cord injury(SCI)induces microglial activation,which leads to prolonged neurological dysfunction.However,the mechanism underlying microglial activation-induced neuroinflammation remains poorly understood.Ruxolitinib(RUX),a selective inhibitor of JAK1/2,was recently reported to inhibit inflammatory storms caused by SARS-CoV-2 in the lung.However,its role in disrupting inflammation post-SCI has not been confirmed.In this study,microglia were treated with RUX for 24 hours and then activated with interferon-γfor 6 hours.The results showed that interferon-γ-induced phosphorylation of JAK and STAT in microglia was inhibited,and the mRNA expression levels of pro-inflammatory cytokines tumor necrosis factor-α,interleukin-1β,interleukin-6,and cell proliferation marker Ki67 were reduced.In further in vivo experiments,a mouse model of spinal cord injury was treated intragastrically with RUX for 3 successive days,and the findings suggest that RUX can inhibit microglial proliferation by inhibiting the interferon-γ/JAK/STAT pathway.Moreover,microglia treated with RUX centripetally migrated toward injured foci,remaining limited and compacted within the glial scar,which resulted in axon preservation and less demyelination.Moreover,the protein expression levels of tumor necrosis factor-α,interleukin-1β,and interleukin-6 were reduced.The neuromotor function of SCI mice also recovered.These findings suggest that RUX can inhibit neuroinflammation through inhibiting the interferon-γ/JAK/STAT pathway,thereby reducing secondary injury after SCI and producing neuroprotective effects.
