Impact of splenic red pulp macrophages on hematopoiesis and their therapeutic effects against sepsis

Patients with sepsis frequently experience dysregulation of hematopoietic function in the bone marrow-spleen axis, resulting in hematologic abnormalities, including anemia and leukopenia. We hypothesized that red pulp macrophages (RPMs) in the spleen contribute to hematopoiesis through the bone marrow–spleen axis in septic patients. We established the sepsis model by cecal ligation and puncture (CLP) surgery, and performed bone marrow transplantation (BMT) and splenic RPMs transplantation (RPMT) after CLP. We evaluated splenic RPMs, hematopoietic stem and progenitor cells (HSPCs; LSK cells), and multipotent progenitor 3 cells (MPP3) proliferation and immunomodulatory properties. We performed splenic transcriptome sequencing (RNA-seq) to uncover the mechanisms by which RPMs exert therapeutic effects against sepsis. Sepsis-induced myelosuppression at 24h and MDSCs accumulation at 72h were detected. Both BMT and RPMT effectively restored splenic RPMs and suppressed MDSCs, with RPMT exerting a greater effect on LSK and MPP3 proliferation. RNA-seq confirmed that both BMT and RPMT attenuated sepsis-associated inflammation. Notably, RPMT exerted more targeted effects on hematopoietic cell lineage, cell cycle progression, and energy metabolism than BMT. This study demonstrates that splenic RPMs play a crucial regulatory role in hematopoiesis through the bone marrow-spleen axis during sepsis.