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.

Nonsubstrate interactions of thrombin with fibrin play an important role in modulating its procoagulant activity. To establish the structural basis for these interactions, we crystallized D-Phe-ProArg-chloromethyl ketone-inhibited human thrombin in complex with a fragment, E ht, corresponding to the central region of human fibrin, and solved its structure at 3.65-Å resolution. The structure revealed that the complex consists of two thrombin molecules bound to opposite sides of the central part of E ht in a way that seems to provide proper orientation of their catalytic triads for cleavage of fibrinogen fibrinopeptides. As expected, binding occurs through thrombin's anion-binding exosite I. However, only part of it is involved in forming an interface with the complementary negatively charged surface of E ht. Among residues constituting the interface, Phe-34, Ser-36A, Leu-65, Tyr-76, Arg-77A, Ile-82, and Lys-110 of thrombin and the A␣ chain Trp-33, Phe-35, Asp-38, Glu-39, the B␤ chain Ala-68 and Asp-69, and the ␥ chain Asp-27 and Ser-30 of E ht form a net of polar contacts surrounding a well defined hydrophobic interior. Thus, despite the highly charged nature of the interacting surfaces, hydrophobic contacts make a substantial contribution to the interaction.