Diflunisal targets the HMGB1/CXCL12 heterocomplex and blocks immune cell recruitment

Federica De Leo, Giacomo Quilici, Mario Tirone, Francesco De Marchis, Valeria Mannella, Chiara Zucchelli, Alessandro Preti, Alessandro Gori, Maura Casalgrandi, Rosanna Mezzapelle, Marco E. Bianchi, Giovanna Musco

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article numbere47788
JournalEMBO Reports
Issue number10
Publication statusPublished - Oct 4 2019


  • CXCL12
  • diflunisal
  • HMGB1
  • inflammation
  • NMR

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics


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