Screening of the FDA-approved drug library identifies CCL17 inhibitors that block arthritic pain

Rheumatoid arthritis (RA) is an inflammatory and destructive autoimmune polyarthritis that causes pain, swelling and deformity in the joints. While clinical trials targeting GM-CSF in RA are showing promise, the potential side effects of anti-GM-CSF therapy highlight the need for identifying downstream mediators of GM-CSF action. CCL17, a downstream inflammatory mediator of GM-CSF in monocytes and macrophages, has been shown to mediate GM-CSF-driven inflammatory arthritis in animal models. CCL17 shares its receptor, CCR4, with CCL22; however, unlike CCL17, CCL22 has been implicated in resolving inflammation. Therefore, drugs that can suppress the formation of CCL17, but not CCL22, may be beneficial in the treatment of inflammatory arthritis. In this study, we screened a panel of 1508 FDA-approved drugs and identified five drugs, namely fluoxetine, ractopamine, ponesimod, terbutaline and etravirine, which potently inhibited CCL17 production without adverse effects on cell viability and CCL22 formation in human monocytes and mouse macrophages. Mechanistically, we demonstrated that these drugs inhibited STAT5 activity and IRF4 expression to suppress CCL17 formation. Significantly, therapeutic administration of these five drugs in an inflammatory arthritis model revealed that fluoxetine, ractopamine, ponesimod and terbutaline could inhibit arthritic pain, correlating with decreased CCL17 expression. Given the need for new and safe anti-inflammatory therapeutics to treat RA and the benefits of repurposing existing drugs for new indications, our findings reported here offer four new promising analgesics for treating inflammatory pain.