Dysregulated CXCL12 Expression in Osteoblasts Promotes B-lymphocytes Preferentially Homing to the Bone Marrow in MRL/lpr Mice

Abstract

Peripheral circulating B-lymphocytes and B-lymphocytes in the bone marrow (BM) show different responses to lymphotoxic or immunosuppressive agents. We explored the existence of a dysregulated distribution of B-lymphocytes between peripheral and BM compartments and the underlying mechanisms. The percentage of CXC chemokine receptor 4+ B (CXCR4+ B) cells was decreased in the peripheral blood (PB) and increased in the BM of MRL/lpr mice and SLE patients. CXC chemokine ligand 12 (CXCL12) production by BM osteoblasts (OBs) derived from MRL/lpr mice and SLE patients was higher than that obtained with C57BL/6 mice or healthy subjects. MRL/lpr-derived OBs demonstrated stronger chemotactic ability toward B-lymphocytes than control OBs, and more B-lymphocytes colocalized with OBs within the periosteal zone in MRL/lpr mice. Moreover, the CXCR4+ B cell percentages were negatively correlated with the serum immunoglobulin G concentration, and the BM CXCL12 levels were positively correlated with the systemic lupus erythematosus disease activity index score and anti-double stranded DNA titer and negatively correlated with the serum complement 3 concentration. In conclusion, our results indicate a shifted distribution of B-lymphocytes between the BM and peripheral compartments in SLE patients and MRL/lpr mice and that the upregulation of CXCL12 in OBs likely contributes to enhanced chemotactic migration and anchorage of B-lymphocytes to OBs.