Single-cell analysis reveals transcriptomic patterns in active macrophage activation syndrome and therapeutic potential of albumin-fused interleukin-10 in a mouse model

Introduction Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperinflammatory conditions. We aimed to characterize immune cell transcriptomic patterns in human MAS and investigate the therapeutic potential of albumin-fused IL-10 protein (SA-IL-10) in a MAS mouse model. Methods We performed single-cell RNA sequencing (scRNA-seq) on bone marrow and peripheral blood samples from patients with newly developed MAS caused by diverse etiologies. We generated paired Seq-Well single-cell transcriptomes from bone marrow and blood of patients with active HLH/MAS. In the absence of a contemporaneous control cohort, technology-matched public Seq-Well marrow and same-laboratory control blood were projected onto the frozen patient atlases as lineage context, not as a case–control comparison. We also evaluated the effect of SA-IL-10 in a CpG-DNA–induced mouse model of MAS. Results Human scRNA-seq identified diverse immune cell populations, including dendritic cells, macrophages, and monocyte subsets. Canonical lineages in the public data were transferred to the expected patient states. Monocyte 1 and macrophage populations expressed transcripts encoding IL-10 receptor subunits and associated signaling molecules, although these findings reflect RNA abundance and do not establish functional responsiveness. Donor-level phagocytosis and interferon-γ programs showed no significant differences after multiple-testing correction. In the mouse model, SA-IL-10 treatment significantly improved anemia, leukocytopenia, splenomegaly, and liver dysfunction and was associated with reduced circulating interferon-γ levels and bone marrow macrophage abundance. Conclusion Human scRNA-seq provides transcriptomic patterns in active HLH/MAS. The therapeutic effects observed in the mouse model support further investigation of SA-IL-10 as a potential treatment for MAS.