〔Abstract〕 Objective To investigate the effects of tryptophan-2,3-dioxygenase(TDO2) on collagen-induced arthritis, the expression of CIA in mice and the specific mechanism by which prostaglandin E2(PGE2) inhibits the expression and activity of TDO2 and thus regulates the function of macrophages. Methods Type Ⅱ collagen induced the CIA model in DBA/1J mice. The ankle joint injury of CIA mice was detected by X-ray. The expression of TDO2 in ankle joint and spleen was detected by immunohistochemistry. Changes of TDO2 expression in peritoneal macrophages(PMs) were detected by qPCR and immunofluorescence. TDO2 expression was detected by small interference in RAW264.7 cells, TDO2 inhibitor 680C91, PGE2 stimulation with different concentrations(0.1, 1, 10 μmol/L) and EP4 receptor agonist CAY10598. qPCR and Western blot were used to detect TDO2 expression. The phagocytosis and polarization of macrophages were detected by flow cytometry. The activity of TDO2 was detected by colorimetry. Results Compared with normal mice, CIA mice had larger soft tissue swelling in ankle, and increased TDO2 expression in synovium, spleen and PMs. In RAW264.7 cells, TDO2 expression was significantly inhibited after small interference, TDO2 inhibitor 680C91, PGE2 stimulation, and EP4 receptor agonist CAY10598, macrophage phagocytosis decreased, and M1/M2 ratio decreased(P<0.05). Colorimetric results showed that the activity of TDO2 was inhibited after stimulation of PGE2 and EP4 agonist CAY10598 in RAW264.7 cells(P<0.05). Conclusion The increased expression of TDO2 in macrophages may promote synovial injury in CIA mice, and PGE2 regulates the function of macrophages by inhibiting the expression and activity of TDO2 by activating EP4 receptor.