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FANCC deficiency mediates microglial pyroptosis and secondary neuronal apoptosis in spinal cord contusion
Mingjie Xia1, Xinyu Li2, Suhui Ye3,4
1Department of Orthopedics, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210029, Jiangsu, China.
Background:
Traumatic spinal cord injury (SCI)-induced neuroinflammation results in secondary neurological destruction and functional disorder. Previous findings showed that microglial pyroptosis plays a crucial role in neuroinflammation. Thus, it is necessary to conduct a comprehensive investigation of the mechanisms associated with post-SCI microglial pyroptosis. The Fanconi Anemia Group C complementation group gene (FANCC) has been previously reported to have an anti-inflammation effect; however, whether it can regulate microglial pyroptosis remains unknown. Therefore, we probed the mechanism associated with FANCC-mediated microglial pyroptosis and neuroinflammation in vitro and in vivo in SCI mice.
Methods:
Microglial pyroptosis was assessed by western blotting (WB) and immunofluorescence (IF), whereas microglial-induced neuroinflammation was evaluated by WB, Enzyme-linked immunosorbent assays and IF. Besides, flow cytometry, TdT-mediated dUTP Nick-End Labeling staining and WB were employed to examine the level of neuronal apoptosis. Morphological changes in neurons were assessed by hematoxylin-eosin and Luxol Fast Blue staining. Finally, locomotor function rehabilitation was analyzed using the Basso Mouse Scale and Louisville Swim Scale.
Results:
Overexpression of FANCC suppressed microglial pyroptosis via inhibiting p38/NLRP3 expression, which in turn reduced neuronal apoptosis. By contrast, knockdown of FANCC increased the degree of neuronal apoptosis by aggravating microglial pyroptosis. Besides, increased glial scar formation, severe myelin sheath destruction and poor axon outgrowth were observed in the mice transfected with short hairpin RNA of FANCC post SCI, which caused reduced locomotor function recovery.
Conclusions:
Taken together, a previously unknown role of FANCC was identified in SCI, where its deficiency led to microglia pyroptosis, neuronal apoptosis and neurological damage. Mechanistically, FANCC mediated microglia pyroptosis and the inflammatory response via regulating the p38/NLRP3 pathway.
Insights
Fanconi Anemia Group C complementation gene (FANCC) deficiency exacerbates spinal cord injury (SCI) by promoting microglial pyroptosis and neuronal apoptosis. FANCC protects against SCI by regulating the p38/NLRP3 pathway.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Spinal cord injury (SCI) triggers neuroinflammation, leading to secondary neurological damage.
- Microglial pyroptosis is a key driver of neuroinflammation post-SCI.
- The anti-inflammatory role of Fanconi Anemia Group C complementation gene (FANCC) in SCI is not well understood.
Purpose of the Study:
- To investigate the role of FANCC in regulating microglial pyroptosis and neuroinflammation after SCI.
- To elucidate the underlying molecular mechanisms of FANCC-mediated pyroptosis in SCI.
Main Methods:
- Western blotting and immunofluorescence assessed microglial pyroptosis and neuroinflammation.
- Neuronal apoptosis was evaluated using flow cytometry and TUNEL staining.
- Locomotor function recovery was analyzed using the Basso Mouse Scale and Louisville Swim Scale in SCI mice.
Main Results:
- FANCC overexpression suppressed microglial pyroptosis by inhibiting p38/NLRP3, reducing neuronal apoptosis.
- FANCC knockdown aggravated microglial pyroptosis, increasing neuronal apoptosis and neurological damage.
- Loss of FANCC in SCI mice resulted in glial scarring, myelin destruction, poor axon outgrowth, and impaired locomotor function.
Conclusions:
- FANCC deficiency exacerbates SCI by promoting microglial pyroptosis, neuronal apoptosis, and neurological damage.
- FANCC plays a protective role in SCI by modulating the p38/NLRP3 pathway, thereby regulating microglial pyroptosis and neuroinflammation.
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