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Diflunisal targets the HMGB 1/ CXCL 12 heterocomplex and blocks immune cell recruitment
Author(s) -
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
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201947788
Subject(s) - immune system , microbiology and biotechnology , chemistry , biology , immunology
Extracellular HMGB 1 triggers inflammation following infection or injury and supports tumorigenesis in inflammation‐related malignancies. HMGB 1 has several redox states: reduced HMGB 1 recruits inflammatory cells to injured tissues forming a heterocomplex with CXCL 12 and signaling via its receptor CXCR 4; disulfide‐containing HMGB 1 binds to TLR 4 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 HMGB 1 at nanomolar concentrations, at least in part by binding directly to both HMGB 1 and CXCL 12 and disrupting their heterocomplex. Importantly, diflunisal does not inhibit TLR 4‐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.