PT  - JOURNAL ARTICLE
AU  - Federica De Leo
AU  - Giacomo Quilici
AU  - Mario Tirone
AU  - Valeria Mannella
AU  - Francesco De Marchis
AU  - Alessandro Preti
AU  - Alessandro Gori
AU  - Maura Casalgrandi
AU  - Rosanna Mezzapelle
AU  - Marco E. Bianchi
AU  - Giovanna Musco
TI  - Diflunisal targets the HMGB1/CXCL12 heterocomplex and blocks immune cell recruitment
AID  - 10.1101/563890
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 563890
4099  - http://biorxiv.org/content/early/2019/03/01/563890.short
4100  - http://biorxiv.org/content/early/2019/03/01/563890.full
AB  - Extracellular HMGB1 triggers inflammation following infection or injury, and supports tumorigenesis in inflammation-related malignancies. HMGB1 has several redox states: reduced HMGB1 recruits inflammatory cells to injured tissues forming a heterocomplex with CXCL12 and signaling via its receptor CXCR4; disulfide-containing HMGB1 binds to TLR4 and promotes inflammatory responses. Here we show that Diflunisal, an aspirin-like nonsteroidal anti-inflammatory drug (NSAID) that has been in clinical use for decades, specifically inhibits in vitro and in vivo the chemotactic activity of HMGB1 at nanomolar concentrations, at least in part by binding directly to both HMGB1 and CXCL12 and disrupting their heterocomplex. Importantly, Diflunisal does not inhibit TLR4-dependent responses. Our findings clarify the mode of action of Diflunisal, and open the way to the rational design of functionally specific anti-inflammatory drugs.