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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.