Two teams at IRIG, Thierry Rabilloud’s ProMIT team at LCBM and Christine Gaboriaud’s team within the CAID group at IBS, 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.
This research is supported by funding from Marie Lorvellec’s EUR thesis and the ANR DYSALARM project.