Targeting the chemokine receptor CXCR4 with histamine analog to reduce inflammation in juvenile arthritis.

Among immune cells, activated monocytes play a detrimental role in chronic and viral-induced inflammatory pathologies, particularly in Juvenile Idiopathic Arthritis (JIA), a childhood rheumatoid arthritis (RA) disease. The uncontrolled activation of monocytes and excessive production of inflammatory factors contribute to the damage of bone-cartilage joints. Despite the moderate beneficial effect of current therapies and clinical trials, there is still a need for alternative strategies targeting monocytes to treat RA. To explore such an alternative strategy, we investigated the effects of targeting the CXCR4 receptor using the histamine analog clobenpropit (CB). Monocytes were isolated from the blood and synovial fluids of JIA patients to assess CB's impact on their production of key inflammatory cytokines. Additionally, we administered daily intraperitoneal CB treatment to arthritic mice to evaluate its effects on circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption, as indicators of disease progression. Our findings demonstrated that CXCR4 targeting with CB significantly inhibited the spontaneous and induced-production of key inflammatory cytokines by monocytes isolated from JIA patients. Furthermore, CB treatment in a mouse model of collagen-induce arthritis resulted in a significant decrease in circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption, leading to a reduction in disease progression. In conclusion, targeting CXCR4 with the small amino compound CB shows promise as a therapeutic option for chronic and viral-induced inflammatory diseases, including RA. CB effectively regulated inflammatory cytokine production of monocytes, presenting a potential targeted approach with potential advantages over current therapies. These results warrant further research and clinical trials to explore the full therapeutic potential of targeting CXCR4 with CB-like molecules in the management of various inflammatory diseases.

Informations de copyright

Copyright © 2023 Bekaddour, Smith, Beitz, Llibre, Dott, Baudry, Korganow, Nisole, Mouy, Breton, Bader-Meunier, Duffy, Terrier, Schneider, Quartier, Rodero and Herbeuval.

Déclaration de conflit d'intérêts

Author PQ reports personal fees from Abbvie, personal fees from BristolMyers Squibb, personal fees from Chugai-Roche, personal fees from Lily, personal fees from Novartis, personal fees from Novimmune, personal fees from sweedish orphan biovitrum, personal fees from Sanofi, outside the submitted work. Authors J-PH and NS have a patent WO2017216373A1 issued. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer FA declared a shared parent affiliation with the author SN to the handling editor at the time of review.