Identification of FAM3D as a new endogenous chemotaxis agonist for the formyl peptide receptors

ABSTRACT The family with sequence similarity 3 (FAM3) gene family is a cytokine-like gene family with four members FAM3A, FAM3B, FAM3C and FAM3D. In this study, we found that FAM3D strongly chemoattracted human peripheral blood neutrophils and monocytes. To identify the FAM3D receptor, we used chemotaxis, receptor internalization, Ca2+ flux and radioligand-binding assays in FAM3D-stimulated HEK293 cells that transiently expressed formyl peptide receptor (FPR)1 or FPR2 to show that FAM3D was a high affinity ligand of these receptors, both of which were highly expressed on the surface of neutrophils, and monocytes and macrophages. After being injected into the mouse peritoneal cavity, FAM3D chemoattracted CD11b+ Ly6G+ neutrophils in a short time. In response to FAM3D stimulation, phosphorylated ERK1/2 and phosphorylated p38 MAPK family proteins were upregulated in the mouse neutrophils, and this increase was inhibited upon treatment with an inhibitor of FPR1 or FPR2. FAM3D has been reported to be constitutively expressed in the gastrointestinal tract. We found that FAM3D expression increased significantly during colitis induced by dextran sulfate sodium. Taken together, we propose that FAM3D plays a role in gastrointestinal homeostasis and inflammation through its receptors FPR1 and FPR2.