Macrophage Polarization, Inflammatory Monocytes, and Impaired MDSCs are Associated with Murine and Human Immune Aplastic Anemia

Abstract Immune-mediated bone marrow failure (BMF) entails a complex immune landscape. Myeloid cells, including monocytes, macrophages, and myeloid-derived suppressor cells (MDSCs), are involved in the development and progression of immune aplastic anemia (AA). We used a murine model of BMF to explore the effects of CSF-1R inhibition on immune pathophysiology. Hematopoiesis, immune cell populations, and gene expression were assessed by flow cytometry, cytokine analysis, and single-cell RNA sequencing. CSF-1R inhibition with the small molecule PLX3397 intensified BMF in CByB6F1 mice, enhancing inflammation and macrophage polarization toward the pro-inflammatory M1 phenotype. This was accompanied by increased leukocyte apoptosis, a reduction in CD11b+ myeloid cells, and worsened animal survival. In contrast, the JAK-inhibitor baricitinib attenuated BMF, promoting M2 macrophage polarization, and decreasing CD8+ T cell infiltration of bone marrow. Single-cell RNA analysis revealed upregulation of M1 signature genes in both murine BMF and also AA human samples. In patients with severe AA, there was a shift towards an M1-like monocyte phenotype, correlating with increased inflammatory cytokine expression and altered MDSC populations. These findings highlight the role of myeloid-derived cells in BMF and suggest that M1 macrophages, with defective MDSC function, contribute to disease pathogenesis and progression. Targeting macrophage polarization or MDSCs offers alternative therapeutic strategies in immune-mediated BMF.