FNDC4 acts as an anti-inflammatory factor on macrophages and improves mouse model of induced colitis. FNDC4 could suppress osteoclast formation via NF-kappaB pathway and downregulation of CXCL1. Analysis of binding of FNDC4 to different immune cell types reveals strong and specific binding to macrophages and monocytes. FNDC4 treatment of bone marrow-derived macrophages in vitro results in reduced phagocytosis, increased cell survival and reduced proinflammatory chemokine expression. Hence, treatment with FNDC4 results in a state of dampened macrophage activity, while enhancing their survival. That FNDC4 may be a factor with direct therapeutic potential in inflammatory bowel disease and possibly other inflammatory diseases.