Abstract
Abstract Mononuclear phagocytes, including monocytes, macrophages, and dendritic cells, function in tissue homeostasis, and also regulate immune responses. Tissue resident macrophages in a variety of tissues arise from the yolk sac, and are generated independently of hematopoietic stem cells. However, the origin of thymic macrophages remains poorly understood. Nr4a1 is an orphan nuclear receptor that limits pro-inflammatory cytokine production in macrophages, and functions as the master regulator of Ly6C- patrolling monocyte development. Here, we report a significant defect in the development of thymic resident macrophages in Nr4a1-deficient animals. Thymic macrophage levels were reduced over two-fold compared with wild-type controls. However, Nr4a1 does not globally regulate the development of tissue macrophages, as macrophages resident in the spleen, lung, brain, pancreas, and peritoneum from Nr4a1-deficient mice develop normally. Moreover, Nr4a1-deficient thymic macrophages fail to clear apoptotic thymocytes in vivo, and express reduced levels of genes important for apoptotic cell engulfment, including engulfment receptors Mertk, and Axl. Defective thymic macrophage development likely impairs proper T cell selection, thus altering the immune system as a whole. Together, these data show that Nr4a1 regulates the development and functional capacity of tissue resident macrophages in the thymus, and provide a novel mechanism for maintenance of thymic homeostasis.
Published Version
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