Resolvin E1 improves efferocytosis and rescues severe aplastic anemia in mice

Abstract Treatments for severe aplastic anemia (SAA) rely on stem cell transplantation and immunosuppressive therapies. Immune-mediated destruction and inflammation drive SAA, but the mechanisms that lead to persistent inflammation are unknown. Using an established mouse model of SAA, we observed increased apoptotic cells within the bone marrow (BM), correlating with impaired efferocytosis. Single-cell transcriptomics revealed heterogeneity among SAA BM monocytes and enhanced inflammatory signatures. Notably, increased expression of Sirpa and Cd47 were observed on monocytes in murine SAA, as well as human SAA patients. The don’t eat me signal CD47 was increased on apoptotic BM cells, concurrent with markedly increased signal regulatory protein alpha (SIRPα) on monocytes. Functionally, SIRPα blockade improved cell clearance and reduced CD47-positive apoptotic cells. Lipidomics 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 mice. Resolvin E1 (RvE1) therapy improved efferocytosis, BM cellularity, platelets, and survival. Our data link impaired efferocytosis with SAA and suggest that failed inflammation resolution contributes to disease progression. We demonstrate that SPMs, such as RvE1, offer novel treatments for SAA that do not rely on immune suppression.