Targeting foamy macrophages by manipulating ABCA1 expression to facilitate lesion healing in the injured spinal cord

Spinal cord injury (SCI) triggers a complex cascade of events, including myelin loss, neuronal damage, neuroinflammation, and the accumulation of damaged cells and debris at the injury site. Infiltrating bone marrow derived macrophages (BMDM phi) migrate to the epicenter of the SCI lesion, where they engulf cell debris including abundant myelin debris to become pro-inflammatory foamy macrophages (foamy M phi), participate neuroinflammation, and facilitate the progression of SCI. This study aimed to elucidate the cellular and molecular mechanisms underlying the functional changes in foamy M phi and their potential implications for SCI. Contusion at T10 level of the spinal cord was induced using a New York University (NYU) impactor (5 g rod from a height of 6.25 mm) in male mice. ABCA1, an ATP-binding cassette transporter expressed by M phi, plays a crucial role in lipid efflux from foamy cells. We observed that foamy M lacking ABCA1 exhibited increased lipid accumulation and a higher presence of lipid-accumulated foamy M as well as elevated pro-inflammatory response in vitro and in injured spinal cord. We also found that both genetic and pharmacological enhancement of ABCA1 expression accelerated lipid efflux from foamy M phi, reduced lipid accumulation and inhibited the pro-inflammatory response of foamy M phi, and accelerated clearance of cell debris and necrotic cells, which resulted in functional recovery. Our study highlights the importance of understanding the pathologic role of foamy M in SCI progression and the potential of ABCA1 as a therapeutic target for modulating the inflammatory response, promoting lipid metabolism, and facilitating functional recovery in SCI.