Mer signal plays the central roles in the intrinsic inhibition of the inflammatory response to pathogens by macrophages and dendritic cells. Liver X receptors (LXRα and LXRβ) also have a role for the maintenance of immune tolerance. However, physiological relevance of endogenous activation and transrepression pathways has remained unclear. In the present study, we aimed to understand the impact of endogenous Mer signal on TLR-dependent generalized inflammatory responses and LXR activation in zymosan-treated mice, using anti-Mer neutralizing antibody. Treatment with anti-Mer antibody significantly reduced phosphorylation of Mer and Akt, Mer downstream molecule in peritoneal macrophages and/or spleen and lung at hours 6, 24, and 72 after zymosan treatment. Anti-Mer antibody inhibited apoptotic cell clearance by peritoneal macrophages in vivo and ex vivo, but further enhanced neutrophil number and the levels of protein in peritoneal cavity. Moreover, anti-Mer antibody enhanced zymosan-induced pro-inflammatory mediators, including TNF-α, IL-1β, MIP-2 and MMP-9, but reduced anti-inflammatory mediators, such as TGF-β and HGF in peritoneal fluid. Similar findings with anti-Mer antibody and zymosan were shown at the levels of genes of TNF-α and MIP-2, as well as TGF-β and HGF in spleen and lung tissue. After zymosan injection, LXRα expression in spleen and lung reduced at 6 hours and reached the control level at 24hours and increased at 72 h. The level of LXRβ expression dropped at 6 hours, reached to the control level at 24 h, and remained at 72 h. The levels of LXRα/β at these time points after injection of zymosan were reduced by treatment with anti-Mer antibody. The levels of genes and proteins of LXRα/β target molecules, such as ABCA1 and ApoE, were in parallel reduced by treatment with anti-Mer antibody. Importantly, co-administration of T0901317 with anti-Mer antibody enhanced LXRs expression and activation and reversed the increases in these pro-inflammatory mediators, neutrophil numbers, and the levels of protein in peritoneal fluid at 6 and 24 h after zymosan injection. These findings suggest that Mer signaling contributes for the resolution of generalized inflammation through upregulation of LXR induction and activation.