Autophagy activation by the Becn1F121A mutation reprograms neuroinflammation and promotes neurological recovery after spinal cord injury

Autophagy is essential for maintaining cellular homeostasis, particularly under stress conditions such as neurotrauma. In experimental models of spinal cord injury (SCI), dysregulated autophagy has been closely associated with secondary injury cascades. Our previous work demonstrated that post-injury inflammation is exacerbated by genetic inhibition of autophagy and alleviated by pharmacological enhancement. Emerging evidence also indicates that SCI can induce neuropathological changes in the brain, leading to cognitive impairments; however, the underlying molecular mechanisms remain largely unclear. In this study, we utilized Becn1^F121A/F121A knock-in (BMut) mice to investigate how genetically enhanced autophagy influences transcriptomic profiles, neural cell responses, tissue pathology, and functional recovery following contusion SCI. Transcriptomic analysis of BMut mouse spinal cord (SPC) tissues at 3 days post-injury revealed enhanced autophagy flux, reduced inflammatory responses, and altered microglial function and immune activity. Ten weeks after injury, BMut mice exhibited distinct transcriptomic profiles in the SPC, somatosensory cortex, and hippocampus. Further analyses revealed that the Becn1^F121A/F121A mutation enhanced autophagy and altered inflammatory responses to SCI across all three regions. Behavioral assessments demonstrated improved functional recovery in BMut mice, accompanied by better-preserved spared white matter and reduced lesion volume. Immunofluorescence staining analysis showed that the Becn1^F121A/F121A mutation reduced microglial activation and enhanced neurogenesis in the hippocampal dentate gyrus. Our study showed that genetic enhancement of autophagy altered transcriptomic responses, particularly inflammation, after SCI, reducing neuropathology in the spinal cord and brain and improving function. This is the first evidence linking autophagy enhancement to modulation of neuroinflammation after SCI, highlighting its therapeutic potential.