CCRL2 deficiency and dyslipidemia: implications for thrombocytopenia post allo-HSCT.

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been the most effective treatment for refractory hematologic diseases. Thrombocytopenia (TP) and dyslipidemia are common complications that affect the prognosis of patients after allo-HSCT. The chemokine (c-c motif) receptor-like 2 (CCRL2) has various roles in immune and inflammatory responses, while its function in thrombopoiesis after allo-HSCT has not been reported. Therefore, this study investigated the role of CCRL2 in thrombopoiesis under conditions of dyslipidemia. Differentially expressed genes in bone marrow-derived nucleated cells were analysed using next-generation RNA sequencing. Enzyme-linked immunosorbent assay (ELISA) was used to detect the concentrations of thrombopoietin (TPO) or chemerin. CCRL2 and ApoE double knockout (CCRL2^-/-ApoE^-/-) mice were generated by crossing CCRL2^-/- mice with ApoE^-/- mice. Inflammatory cytokines, megakaryocyte (MK) polyploidization, and reactive oxygen species (ROS) levels were assessed by flow cytometry. Giemsa staining of human bone marrow smears and hematoxylin and eosin (H&E) staining of paraffin-embedded murine bone marrow slices were performed to identify MK morphology. Immunoblotting was employed to analyze autophagic protein levels by detecting LC3. CCRL2 was significantly downregulated in platelets and MKs of TP children with impaired megakaryopoiesis, severe dyslipidemia, and strong cytokine storms. Platelet counts and high-ploidy MKs in CCRL2^-/-ApoE^-/- mice were significantly reduced compared to CCRL2^+/+ApoE^-/- and CCRL2^+/+ApoE^+/+ mice, accompanied by decreased ROS levels and increased autophagic protein expression. Our results demonstrated that both CCRL2 and lipid homeostasis are closely related to thrombopoiesis, and may provide potential targets for the prevention of TP after allo-HSCT.