Effects of procalcitonin on macrophages during sepsis

Objectives Sepsis is a severe and life-threatening disease that causes the death of around 6 million people worldwide every year. It represents not only a frequent complication following trauma but also a significant problem following joint arthroplasty. In around 1-5% of primary and in 3-15% of revision arthroplasties periprosthetic joint infections occur that can potentially end up in sepsis. Since sepsis dramatically increases mortality risk of affected patients, and as there are only limited treatment options to date, new therapeutic targets need to be identified. In this regard, the common sepsis marker procalcitonin (PCT), is of high interest, as PCT blood levels correlate with disease severity. However, as the molecular link between PCT and sepsis progression is not known, the understanding of the underlying mechanisms could lead to the development of new drugs to treat sepsis.

Methods To unravel the role of PCT in sepsis, Calca-deficient mice lacking PCT received intraperitoneal injections of 40 mg/kg lipopolysaccharides (LPS). Survival was monitored in comparison to LPS-treated wild type C57Bl/6 mice. Organs were harvested for histological and cellular analyses. For in vitro investigations, bone marrow-derived stem cells were isolated from wild type mice and differentiated into macrophages through stimulation with macrophage colony-stimulating factor (M-CSF) for one week.

Thereafter, macrophages where treated with LPS, PCT or a combination of both, and cell migration assays as well as mRNA expression profiling through gene chip analysis were performed.

Results and Conclusion In vivo, Calca-deficient mice, lacking PCT expression, showed a significantly improved survival following septic shock through LPS injection compared to wild type controls, pointing towards a negative effect of PCT on sepsis outcome. Furthermore, Calca-deficient mice displayed a decreased number of macrophages and dendritic cells in the lung after LPS treatment than wild type mice, suggesting a specific impact of PCT on the migration of these cells. In vitro, treatment of macrophages with LPS and PCT resulted in a potent inhibitory effect of PCT on macrophage migration. Moreover, gene chip analysis revealed that PCT significantly alters the expression of several key factors involved in macrophage migration. This study demonstrates for the first time a functional link between PCT and macrophage function and migration during sepsis. Further analysis of M1 and M2 subtypes including intracellular metabolism (Seahorse technique) and investigation of downstream effects of PCT in macrophages may reveal promising new targets to improve outcomes of septic patients.

Stichwörter Procalcitonin, PCT, sepsis, macrophages, LPS

Publication History

Article published online:
15 October 2020