The absence of the adaptor proteins CARDIF/STING negatively regulates the prolfieration of liver regeneration after partial hepatectomy in mice

Abstract

Background: Nucleic acid sensors are known to play a major role during liver regeneration, however, there is only limited knowledge on the role of central adaptor proteins, such as CARDIF and STING. Our hypothesis states that these modulators of the innate immune system have an influence on liver regeneration. Methods: We use a newly established CARDIF/STING knockout mouse model and a C57BL/6 control cohort. A 2/3 partial hepatectomy (PH) was performed in both groups (n=60 mice in total). Liver regeneration was quantified by liver-to-body weight ratio, proliferation was determined by BrdU staining, RNA- and protein levels of proliferation markers were analyzed in resected tissues and pro-inflammatory cytokines were measured in murine serum. Results: CARDIF/STING knockout mice showed a significantly impaired liver regeneration after PH. Expression analysis of Interleukin-6 revealed a significant decrease in the wild type cohort after PH. In CARDIF/STING knockout mice, the proliferation marker Cyclin D1 was decreased until 24 hours after surgery, while p21Cip1 expression was increased 8h post-PH. Conclusion: Together, these data provide the first experimental evidence that CARDIF/STING knockout mice show a delayed liver regeneration. In the absence of these two proteins, we observed a modulated immune response which lead to a negative regulation of the proliferative capacity after partial hepatectomy. This finding could impact on the future development of molecular therapies making use of the innate immune system.