Daptomycin alleviates collagen-induced arthritis via suppressing inflammatory cytokines and NF-κB pathway

•DAP inhibits secretion of IL-1β, IL-6, and TNF-α to alleviate cellular inflammation.•DAP exerts an anti-inflammatory effect by inhibiting p65 phosphorylation in the NF-κB pathway and blocking its nuclear translocation.•DAP treatment can effectively relieve arthritis symptoms in CIA mice without obvious toxicity. Rheumatoid arthritis (RA) is a chronic autoimmune disease, and its pathogenic factors include bacterial infection and immune inflammation. Daptomycin (DAP) is a cyclic lipopeptide that has been approved to treat skin infections, bacteremia and right-sided endocarditis due to its effective antibacterial effects against most Gram-positive pathogenic bacteria. Herein, we focus on whether DAP exerts anti-inflammatory activity on RA to expand DAP drug indications. Our studies are first time to evaluate anti-inflammatory effect and reveal its molecular pharmacological mechanism of DAP on lipopolysaccharide-activated macrophage and collagen-induced arthritis (CIA) mice. In vitro cytological studies show that 10 µg/mL DAP inhibits secretion of IL-1β, IL-6 and TNF-α to alleviate cell inflammation, and the phosphorylation level of p65 (p-p65) of RAW 264.7 cells is decreased under DAP exposure. Administration with 10 mg/kg/2d DAP via intravenous injection on CIA mice significantly reduces arthritis symptom by inhibiting p-p65 level and decreasing serum level of IL-6, IL-1β and TNF-α. Moreover, our study is the first time to reveal new immunomodulatory effects of DAP on RA, which provides a pharmacological basis for new clinical applications of DAP for other immune-related diseases except to bacterial infections.