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In the United States approximately 17,000 new spinal cord injury cases occur annually. Even with timely medical interventions, the primary injury is often exacerbated by a period of inflammation and pathological vascular changes that result in additional secondary tissue injuries. Moreover, significant cellular death in the injured cord produces cell debris that can contribute to secondary damage if not promptly cleared. Our investigations demonstrate that bone marrow-derived macrophages (BMDMs), but not resident microglia, are the primary phagocytes that clear cell debris from the injured cord. Furthermore, BMDM are retained in the lesion epicenter for protracted periods of time following engulfment of myelin debris. The BMDMs subsequently become myelin laden macrophages which are detrimental to recovery. To study the effects of myelin debris on macrophages, we have developed in vitro methods that allow the quantification of myelin debris phagocytosis and lipid retention. We also identified myelin debris as a potent non-canonical survival factor that can support long-term BMDM survival and prolong their potential to induce damage in vivo. Moreover, we demonstrate for the first time that myelin basic protein (MBP), is sufficient to suppress BMDM apoptosis. To explore both the inflammatory activation and survival of BMDMs we used RNA-sequencing to profile the transcriptome of BMDMs treated with myelin debris and MBP as well as pro-inflammatory (M1) and anti-inflammatory (M2) stimuli. Pathway analysis reveals several key anti-apoptotic genes up-regulated by both myelin debris and MBP. These represent potential therapeutic targets to reduce prolonged macrophage presence in the lesion. We additionally found that myelin debris stimulated macrophages, while functionally pro-inflammatory, have a transcriptional profile that is distinct from classic M1 macrophages. Collectively, these findings expand our understanding of infiltrating BMDMs in SCI, and reveal novel targets for therapeutic manipulation of immune responses to limit secondary injuries and promote recovery.