HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4

Schiraldi, Milena; Raucci, Angela; Martínez Muñoz, Laura; Livoti, Elsa; Celona, Barbara; Venereau, Emilie; Apuzzo, Tiziana; De Marchis, Francesco; Pedotti, Mattia; Bachi, Angela; Thelen, Marcus; Varani, Luca; Mellado, Mario; Proudfoot, Amanda; Bianchi, Marco Emilio; Uguccioni, Mariagrazia

doi:10.1084/jem.20111739

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Journal article

HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4

Schiraldi, Milena Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Raucci, Angela Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy - HMGBiotech S.r.l., 20133 Milan, Italy
Martínez Muñoz, Laura Department of Immunology and Oncology, National Center for Biotechnology, Spanish National Research Council, 28049 Madrid, Spain
Livoti, Elsa Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Celona, Barbara HMGBiotech S.r.l., 20133 Milan, Italy
Venereau, Emilie Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy
Apuzzo, Tiziana Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
De Marchis, Francesco Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy
Pedotti, Mattia Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Bachi, Angela Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy
Thelen, Marcus Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Varani, Luca Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Mellado, Mario Department of Immunology and Oncology, National Center for Biotechnology, Spanish National Research Council, 28049 Madrid, Spain
Proudfoot, Amanda Merck Serono S.A., 1202 Geneva, Switzerland
Bianchi, Marco Emilio Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy - Vita-Salute San Raffaele University, 20132 Milan, Italy
Uguccioni, Mariagrazia Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland

27.02.2012

Published in:

The journal of experimental medicine. - 2012, vol. 209, no. 3, p. 551-563

English After tissue damage, inflammatory cells infiltrate the tissue and release proinflammatory cytokines. HMGB1 (high mobility group box 1), a nuclear protein released by necrotic and severely stressed cells, promotes cytokine release via its interaction with the TLR4 (Toll-like receptor 4) receptor and cell migration via an unknown mechanism. We show that HMGB1- induced recruitment of inflammatory cells depends on CXCL12. HMGB1 and CXCL12 form a heterocomplex, which we characterized by nuclear magnetic resonance and surface plasmon resonance, that acts exclusively through CXCR4 and not through other HMGB1 receptors. Fluorescence resonance energy transfer data show that the HMGB1–CXCL12 heterocomplex promotes different conformational rearrangements of CXCR4 from that of CXCL12 alone. Mononuclear cell recruitment in vivo into air pouches and injured muscles depends on the heterocomplex and is inhibited by AMD3100 and glycyrrhizin. Thus, inflammatory cell recruitment and activation both depend on HMGB1 via different mechanisms.

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