Identification of FAM3D as a novel endogenous chemotaxis agonist for the FPRs (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 FAM3D receptor, we used chemotaxis, receptor internalization, calcium flux and radioligand-binding assays in FAM3D-stimulated HEK293 cells that transiently expressed FPR1 or FPR2 to show that FAM3D was a high affinity ligand of formyl peptide receptors (FPR1 and FPR2), both of which were highly expressed on the surface of neutrophils and monocytes/macrophages. After being injected into the mouse peritoneal cavity, FAM3D chemoattracted CD11b+Ly6G+ neutrophils in a short time. In response to FAM3D stimulation, p-ERK and p-p38 were up-regulated in the mouse neutrophils, which could be inhibited by an inhibitor of FPR1 or FPR2. FAM3D was reported to be constitutively expressed in the gastrointestinal tract. We found that FAM3D expression increased significantly in dextran sulfate sodium-induced colitis. Taken together, we propose that FAM3D plays a role in gastrointestinal homeostasis and inflammation through its receptors FPR1 and FPR2.