Potential dichotomous role of the antimicrobial peptide LL-37 on immunometabolism during SIRS and Sepsis

• Applicant: Max Hübner, Ph.D.
• Subject Area: Anaesthesiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 542908663

In the context of acute inflammation such as SIRS and sepsis, in addition to an acute inflammatory immune reaction, the immune system mounts a more prolonged anti-inflammatory reaction that leads to an immunoparalysis, especially of the adaptive immune system with variable intensity and duration. Here, the exact mechanisms are not yet fully understood. SIRS and Sepsis are difficult to distinguish from each other, as there are currently no reliable diagnostic markers. In a previous publication, we were able to show that Myeloid-Derived Suppressor Cells are strong mediators of the observed immune. A subsequent investigation of gene expression profiles using Next-Generation Sequencing identified LL-37 as a highly expressed peptide in MDSC. The antimicrobial effect of LL-37 is based on its strong positive charge, which allows it to be integrated into negatively charged bacterial membranes. Thereafter, LL-37 perforates the membrane and lyses the cell. Mitochondria, also identified as bacteria according to the endosymbiotic theory, also possess a strong charge due to their electron transport chain synthesizing ATP. Therefore, the present project aims to investigate the extent to which LL-37 alters T cell metabolism by incorporation into the mitochondrial membrane, reduces essential effector functions of the T cell and thus contributes to immunoparalysis in sterile inflammation. In addition, we aim to clarify whether bacterial presence -at it is the case in sepsis- can reduce the immunoparalytic effect of LL-37. This would, for the first time, describe a dichotomous role of an antibacterial peptide in sterile inflammation (SIRS) and sepsis and could improve and the understanding of pathophysiologists and enable the development of new diagnostic and therapeutic strategies.

• DFG Programme: Research Grants