Summary Effective clearance of apoptotic cells by macrophages is essential for immune homeostasis. The transcriptional pathways that allow macrophages to sense and respond to apoptotic cells are poorly defined. We demonstrate here that LXR signaling is important for both apoptotic cell clearance and the maintenance of immune tolerance. Apoptotic cell engulfment activates LXR and thereby induces the expression of Mer, a receptor tyrosine kinase critical for phagocytosis. LXR null macrophages exhibit a selective defect in phagocytosis of apoptotic cells and an aberrant pro-inflammatory response to them. As a consequence of these defects, mice lacking LXRs manifest a breakdown in self-tolerance and develop autoantibodies and autoimmune glomerulonephritis. Treatment with an LXR agonist ameliorates disease progression in mouse models of Lupus-like autoimmunity. Thus, activation of LXR by apoptotic cells engages a virtuous cycle that promotes their own clearance and couples engulfment to the suppression of inflammatory pathways.

Macrophages are professional phagocytic cells that orchestrate innate immune responses and display remarkable phenotypic diversity at different anatomical locations. However, the mechanisms that control the heterogeneity of tissue macrophages are not well characterized. Here, we report that the nuclear receptor LXRα is essential for the differentiation of macrophages in the marginal zone (MZ) of the spleen. LXR deficient mice are defective in the generation of MZ and metallophilic macrophages, resulting in abnormal responses to blood-borne antigens. Myeloid specific expression of LXRα or adoptive transfer of wild-type monocytes rescues the MZ microenvironment in LXRα deficient mice. These results demonstrate that LXRα signaling in myeloid cells is crucial for the generation of splenic MZ macrophages and reveal an unprecedented role for a nuclear receptor in the generation of specialized macrophage subsets.