Caldecrin was previously isolated as a serum calcium-decreasing factor from the pancreas and is known to suppress receptor activator of nuclear factor-kappa B ligand (RANKL)-induced calcium oscillation pathways in osteoclasts. Here, we explored the effects of caldecrin on lipopolysaccharide (LPS)-Toll-like receptor-4 (TLR-4) signaling pathways in macrophages. Caldecrin inhibited the LPS-induced gene expression of proinflammatory cytokines and M1 macrophage polarization in mouse bone marrow macrophages and the RAW264.7 mouse macrophage cell line. Next, we focused on triggering receptor expressed in myeloid cells-2 (TREM-2) as a co-receptor common to RANKL receptor and TLR-4, and established Trem2-KO RAW264.7 cells, in which Trem2 gene was deleted using the CRISPR/Cas9 system. Caldecrin-mediated alterations in pro-inflammatory cytokine expression and M1 macrophage polarization were not observed in Trem2-KO RAW264.7 cells. These results suggest that caldecrin is not only an inhibitor of osteoclast activation but also a negative regulator of LPS-induced inflammatory responses, functioning via TREM-2. (C) 2020 Elsevier Inc. All rights reserved.