Activating Inflammation Resolution Programs Improves Immunosuppressive Therapy and Prevents Toxicity in Autoimmune Bone Marrow Failure 2267406
Chronic inflammatory and autoimmune diseases are among the leading causes of morbidity and mortality worldwide, yet immunosuppressive therapy (IST) often fails to achieve durable remission and induces toxicity. Severe aplastic anemia (SAA) is a lethal bone marrow failure driven by autoreactive T cells. Patients treated with cyclosporine A (CsA) exhibit sustained inflammation, frequent relapse, and secondary complications. Specialized pro-resolving lipid mediators, such as Resolvin E1 (RvE1), promote resolution of inflammation and restore tissue homeostasis. Using a preclinical murine model, we examined how immunosuppressive and resolution-targeted therapies shape disease outcomes, and whether their combination improves recovery. SAA was induced in sub-lethally irradiated mice via MHC-mismatched splenocyte transfer. Mice were treated with 10 mg/kg CsA and/or 0.0125 mg/kg RvE1 after disease onset. Long-term recovery was assessed 30-90 days post-withdrawal. scRNAseq, ligand-receptor analyses, receptor knockouts, and reciprocal chimeras were used to determine cell-specific mechanisms. CsA improved survival (75%), but caused persistent T cell activation, Th17 expansion, granulocytic skewing, and renal toxicity. Conversely, RvE1 (50% survival) normalized T cells and restored hematopoietic output without organ injury. Combination therapy achieved 100% survival, restored immune profiles, and prevented systemic toxicity. ChemR23 on immune cells was required for RvE1 protection. scRNAseq revealed CsA-induced transcriptional dysregulation, inflammatory cell-cell crosstalk, and aberrant histone gene expression, consistent with durable immune remodeling. RvE1 co-therapy normalized these transcriptional networks. CsA impairs inflammation resolution and long-term organ function. Co-treatment with RvE1 restores immune and hematopoietic homeostasis, supporting integration of pro-resolving therapy with IST for safer, durable remission for autoimmune and inflammatory diseases. CDMRP Bone Marrow Failure Research Program-IDA (BM190079 and BM220031) and NHLBI R01HL159411 Therapeutic Approaches to Autoimmunity (THER)