Macrophage activation and persistent inflammation contribute to the pathological process of spinal cord injury.It was previously reported that M2 macrophage phenotype was induced early (3-7 days) after SCI but M2 markers was reduced or eliminated after 1 week.By contrast,an M1 macrophage response is rapidly induced and then maintained at sites of injured spinal cord.However,factors that modulate macrophage phenotypic and functional change are poorly understood.We developed a model to distinguished bone marrow derived macrophages (BMDMs) from residential microglia and explored how BMDMs change their phenotype and functions in response to the lesion-related factors in injured spinal cord.Infiltrating bone marrow derived macrophages migrate to the epicenter of injury,while microglia distribute to the edges of lesion.Myelin debris at the lesion site switches BMDMs from M2 phenotypes towards M1-like phenotype.In vitro assay showed that myelin debris activate ATP-binding cassette transporter A1 (ABCA1) for cholesterol efflux in response to myelin debris loading.However,in the injured spinal cord,this homeostatic mechanism is overwhelmed,leading to the development of foamy macrophages and lipid plaque in the lesion site.The persistence of these cells indicates a pro-inflammatory environment,associated with enhanced neurotoxicity and impaired wound healing.These foamy macrophages have poor capacity to phagocytose apoptotic cells such as neutrophils resulting in undigested neutrophils releasing their toxic contents and further tissue damage.In conclusion,these data demonstrate for the first time that myelin debris generated in injured spinal cord modulates macrophage activation and function.In light of these findings,we propose that dysregulation of lipid clearance following macrophage phenotype switch contributes to the of spinal cord injury pathology.