Impaired inflammation resolution in murine bone marrow failure is rescued by Resolvin E1 treatment

Abstract Current treatments for severe aplastic anemia (SAA) rely on hematopoietic stem cell (HSC) transplantation and immunosuppressive therapies, however these treatments are not always effective. While immune-mediated destruction and inflammation are known drivers of SAA, the underlying mechanisms that lead to persistent inflammation are unknown. Using an established mouse model of SAA, we observed a significant increase in apoptotic cells within the bone marrow (BM) and demonstrate impaired efferocytosis in SAA mice, as compared to radiation controls. Single-cell transcriptomic analysis revealed heterogeneity among BM monocytes and unique populations emerged during SAA characterized by increased inflammatory signatures and significantly increased expression of Sirpa and Cd47 . CD47, a “don’t eat me” signal, was increased on both live and apoptotic BM cells, concurrent with markedly increased expression of signal regulatory protein alpha (SIRPα) on monocytes. Functionally, SIRPα blockade improved cell clearance and reduced accumulation of CD47-positive apoptotic cells. Lipidomic analysis revealed a reduction in the precursors of specialized pro-resolving lipid mediators (SPMs) and increased prostaglandins in the BM during SAA, indicative of impaired inflammation resolution. Specifically, 18-HEPE, a precursor of E-series resolvins, was significantly reduced in SAA-induced mice relative to radiation controls. Treatment of SAA mice with Resolvin E1 (RvE1) improved efferocytic function, BM cellularity, platelet output, and survival. Our data suggest that impaired efferocytosis and inflammation resolution contributes to SAA progression and demonstrate that SPMs, such as RvE1, offer new and/or complementary treatments for SAA that do not rely on immune suppression. Key Points – IFNγ impairs efferocytosis in SAA, correlating with increased SIRPa hi monocytes and increased CD47 expression – Pro-inflammatory and pro-resolving lipid mediators are imbalanced in SAA, and RvE1 treatment improved efferocytosis and disease outcomes