Diflunisal targets the HMGB1/CXCL12 heterocomplex and blocks immune cell recruitment. (14th August 2019)

• Record Type: Journal Article
• Authors: De Leo, Federica; Quilici, Giacomo; Tirone, Mario; De Marchis, Francesco; Mannella, Valeria; Zucchelli, Chiara; Preti, Alessandro; Gori, Alessandro; Casalgrandi, Maura; Mezzapelle, Rosanna; Bianchi, Marco E; Musco, Giovanna
• Is Part Of: EMBO reports. Volume 20:Number 10(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-08-14
• Subjects: CXCL12 -- diflunisal -- HMGB1 -- inflammation -- NMR; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201947788
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: 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. Synopsis: Interfering with the formation of the HMGB1‐CXCL12 heterocomplex with small molecules is challenging due to limited drug accessibility of the large and flat interfaces of protein‐protein interactions. This study shows that diflunisal, which is a nonsteroidal anti‐inflammatory drug used in the clinic, selectively inhibits the chemotactic activity of HMGB1/CXCL12 heterocomplex without affecting HMGB1/TLR4/MD‐2 signaling and CXCL12 induced cell migration. Diflunisal binds to HMGB1‐CXCL12 complex and inhibits HMGB1/CXCL12/CXCR4 inflammatory axis selectively. Diflunisal is a potent inhibitor of inflammatory cell recruitment by HMGB1 in vitro and in vivo . Diflunisal binds to CXCL12 but does not inhibit CXCL12‐induced cell migration. Diflunisal does not affect TLR4/MD‐2 signaling induced by oxidized form of HMGB1. Abstract : Diflunisal, which is a drug in use in the clinic, selectively inhibits the chemotactic activity of HMGB1/CXCL12 complex.