HMGB1 cleavage by complement C1s and its potent anti-inflammatory product

Researchers at the Institute of Structural Biology (IBS), in collaboration with the Laboratory of Metal Chemistry and Biology (LCBM), are investigating how the immune system responds when it encounters a threat. They are studying how certain substances, known as "alarmins," communicate with the complement defense system to alert and assist in repairing damage once the threat is under control. In their work, they are focusing on HMGB1, a protein normally located in the cell nucleus. However, it is perceived as a danger signal in the extracellular environment.
Furthermore, a previous study has shown that when this protein is cleaved by the C1s protease of the complement system, the pro-inflammatory function of HMGB1 is significantly affected in the context of macrophages activated by lipopolysaccharides (LPS).

To elucidate the underlying molecular mechanism, they have determined the precise cleavage sites of HMGB1 by C1s. The functional impact of the released N-terminal fragments was then studied by monitoring the concentration of pro-inflammatory cytokines (IL-6 and TNFα) in the supernatant of LPS-activated macrophages.

Their results revealed that the small N-terminal fragment F3 (HMGB1 1-65) is capable of significantly reducing the amount of IL-6 secreted by macrophages. This F3 fragment also proved to be a better inhibitor than the A-box fragment of HMGB1, which is currently used as an inhibitor of the full-length protein in the literature. In addition to these findings, they also observed that the cleavage of HMGB1 is modulated by its redox state, depending on how the protein is released : actively secreted by immune cells or passively released after cell death.

In summary, this study demonstrates how alarmins and the complement system communicate to regulate immune system activation and highlights the potential of the C1s protease in inflammation modulation, providing valuable insights for future research.

All of this research is the result of collaboration between two teams at IRIG, Christine Gaboriaud’s team within the CAID group at IBS, and Thierry Rabilloud’s ProMIT team at LCBM, supported by funding from Marie Lorvellec’s EUR thesis and the ANR DYSALARM project.

HMGB1 cleavage by complement C1s and its potent anti-inflammatory product. Lorvellec M, Chouquet A, Koch J, Bally I, Signor L, Vigne J, Dalonneau F, Thielens NM, Rabilloud T, Dalzon B, Rossi V, Gaboriaud C. Frontiers in Immunology 2023 ; 14:1151731. doi : 10.3389/fimmu.2023.1151731.

Contact : Christine Gaboriaud (IBS/Complement, antibodies and infectious disease Group)