Increased Hematopoietic Cells in the mertk−/− Mouse Peritoneal Cavity: A Result of Augmented Migration

The peritoneal cavity is recognized as an important site for autoreactive B cells prior to their transit to other immune tissues; however, little is known of the genes that may regulate this process. Mice lacking the receptor tyrosine kinase, Mertk, display a lupus-like autoimmune phenotype with splenomegaly and high autoantibodies titers. In this study, we investigate whether Mertk regulates the composition of peritoneal cells that favor an autoimmune phenotype. We found an increase in the number of macrophages, dendritic cells (DCs), plasmacytoid DCs, T cells, and B cells in the peritoneal cavity of mertk−/− mice when compared with wild-type mice. This disparity in cell numbers was not due to changes in cell proliferation or cell death. In adoptive transfer experiments, we showed an increase in migration of labeled donor cells into the mertk−/− peritoneal cavity. In addition, bone marrow chimeric mice showed hematopoietic-derived factors were also critical for T cell migration. Consistent with this migration and the increase in the number of cells, we identified elevated expression of CXCL9, its receptor CXCR3, and IL-7R on peritoneal cells from mertk−/− mice. To corroborate the migratory function of CXCR3 on cells, the depletion of CXCR3 donor cells significantly reduced the number of adoptively transferred cells that entered into the peritoneum of mertk−/− mice. This control of peritoneal cells numbers correlated with autoantibody production and was exclusively attributed to Mertk because mice lacking other family members, Axl or Tyro 3, did not display dysregulation in peritoneal cell numbers or the autoimmune phenotype.