Abstract
Lactoferrin (Lf) is widely distributed in mammalian milk, various tissues, and their exocrine fluids and has many physiological functions, such as bacteriostasis, antivirus, and immunoregulation. Here, we provide evidence that lactoferrin is required for early stages of B cell development in mice. Lactoferrin-deficient (Lf(-/-)) C57BL/6 mice showed systematic reduction in total B cells, which was attributed to the arrest of early B cell development from pre-pro-B to pro-B stage. Although the Lf(-/-) B cell "seeds" generated greater pro-B cells comparing to wild type (WT) littermates, the Lf(-/-) mice bone marrow had less stromal cells, and lower CXCL12 expression, produced a less favorable "microenvironment" for early B cell development. The underlying mechanism was mediated through ERK and AKT signalings and an abnormality in the transcription factors related to early differentiation of B cells. The Lf(-/-) mice also displayed abnormal antibody production in T cell-dependent and T cell-independent immunization experiments. In a pristane-induced lupus model, Lf(-/-) mice had more serious symptoms than WT mice, whereas lactoferrin treatment alleviated these symptoms. This study demonstrates a novel role of lactoferrin in early B cell development, suggesting a potential benefit for using lactoferrin in B cell-related diseases.