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

Severe aplastic anemia (SAA) is an acquired form of bone marrow failure characterized by a profound loss of hematopoietic stem cells and failure to produce blood and immune cells. T cells are well-known drivers of disease, though underlying mechanisms causing persistent inflammation remain unknown. Typically, inflammation resolves via an active process mediated by specialized pro-resolving mediators (SPMs), such as resolvins. SPMs dampen inflammation without compromising host immunity, in part, through their ability to induce efficient clearance of apoptotic cells by phagocytes (i.e., efferocytosis). In a murine model of SAA, we identify a novel population of marrow monocytes that co-express the efferocytic receptor MerTK and the inhibitory receptor SIRPα. At the same time, the marrow contained a significant increase in apoptotic and dead cells that expressed the 'don't eat me' marker CD47. Myeloid cells from the marrow of SAA-induced mice exhibited reduced phagocytosis and efferocytosis, relative to controls. Consistent with impaired resolution responses, lipidomic analysis of the marrow revealed an imbalance of pro-inflammatory to pro-resolving lipid mediators. Specifically, we observed significantly reduced 18-hydroxyeicosapentaenoic acid (18-HEPE), a precursor to the E-series resolvins, followed by markedly increased prostaglandins and thromboxane in SAA. Treatment with exogenous Resolvin E1 (RvE1) increased BM cellularity, platelet count, and survival in SAA-induced mice, correlating with improved efferocytotic function. Our findings suggest that defective resolution pathways contribute to disease progression in SAA and demonstrate that SPMs, such as RvE1, may offer new strategies to treat disease that do not rely on immune suppression.