Resolvin E1 limits cyclosporine-induced toxicity and drives durable recovery in autoimmune bone marrow failure

Chronic inflammatory diseases are among the leading causes of morbidity and mortality worldwide, yet conventional immunosuppressive therapies (IST) often fail to achieve durable remission and can cause systemic toxicity. Severe aplastic anemia (SAA), a lethal autoimmune disease and bone marrow failure disorder, exemplifies this challenge with its first-line therapy Cyclosporine A (CsA). CsA suppresses pathogenic T cells and partially restores hematopoiesis in the context of murine SAA, but is associated with nephrotoxicity, hepatotoxicity, and increased Th17 cells one month post-treatment. Conversely, the pro-resolving lipid mediator Resolvin E1 (RvE1) prevents SAA-induced mortality, while also reducing inflammatory immune activation and preserving tissue homeostasis. Treatment with both CsA and RvE1 achieved 100% survival, restored hematopoietic and immune homeostasis, and mitigated CsA-induced toxicity. Mechanistically, RvE1 required the GPCR ChemR23 on immune cells to reverse CsA-induced inflammation and immune dysregulation. To better understand the mechanisms by which CsA drives long-term toxicity and immune dysfunction, and how RvE1 reverses such, we performed single-cell RNA sequencing on total bone marrow from SAA-induced mice one-month post therapy with 10mg/kg CsA and/or 0.00125mg/kg RvE1.