The ability of chemokines to form heterocomplexes with other chemokines or HMGB1 represents an additional level of regulation for shaping their function by enhancing their potency on their cognate receptor. In recent years, the relevance of the CXCL12/HMGB1 heterocomplex activity, on the chemokine receptor CXCR4, has been widely demonstrated in models of inflammation and tissue regeneration, and in human pathological conditions.
Our disclosure of the activity of the CXCL12/HMGB1 heterocomplex in Rheumatoid Arthritis, and the fact that it induces a different conformational change in CXCR4 dimers compared to stimulation with CXCL12 alone, prompted us to further investigate the downstream signalling events elicited by CXCR4 triggering.
In the current work, we demonstrate that the CXCL12/HMGB1 heterocomplex is a balanced agonist for CXCR4, promoting a prompt availability of CXCR4 on the cell surface, and enhancing directional cell migration. These data unveil the signalling induced by the CXCL12/HMGB1 heterocomplex in view of identifying biased antagonists targeting the heterocomplex selective pathways, leaving unaltered the beneficial activity of CXCL12, in order to improve therapies in pathologic conditions. Moreover, the knowledge of the signalling pathways elicited by the heterocomplex could be also relevant in understanding how to foster a CXCR4 signalling able to induce tissue regeneration.
D’Agostino, G., M. Artinger, M. Locati, L. Perez, D. F. Legler, M. E. Bianchi, C. Rüegg, M. Thelen, A. Marchese, M. B. L. Rocchi, V. Cecchinato and M. Uguccioni
Frontiers in Immunology. 2020; 11: DOI: 10.3389/fimmu.2020.550824