Cytosolic nucleic acid sensors of the innate immune system promote liver regeneration after partial hepatectomy

Introduction: DNA sensors localized in the cytosol require the adapter protein STING for the generation of immune responses, while cytosolic RNA sensors use MAVS for signal transduction. Although stimulation of cytosolic nucleic acid sensors by pathogen-derived nucleic acids are important for initiating anti-microbial defense, inadvertent stimulation through self-derived nucleic acids may contribute to autoinflammation and cancer. Methods: Mice with a combined homozygous deficiency of MAVS and STING underwent partial hepatectomy at the age of 10 to 12 weeks. After surgery, we determined liver-to-body-weight ratio and performed BrdU labeling as well as immunohistochemistry. In addition, we performed Western blotting for p-STAT3, p-RB, p-CDK2, cyclin E1, cyclin D1, and CDK1 as well as quantitative RT-PCR for p21 and SOCS3. Results: Our analysis directly demonstrated that defective cytosolic nucleic acid sensing impairs hepatocyte proliferation and delays the recovery of organ mass. Whereas combined MAVS and STING deficiency did not influence upregulation of the G1 phase cyclins D1 and E1, it substantially reduced the hyperphosphorylation of RB protein, attenuated the activating phosphorylation of CDK2, and impaired both CDK1 upregulation and hepatocyte BrdU incorporation. Importantly, expression of the cell cycle inhibitor p21 was markedly elevated in mutant as compared with wildtype mice. Conclusions: Here, we report on a previously unrecognized role of cytosolic nucleic acid sensors for organ regeneration. Our findings suggest that deficiency of cytosolic nucleic acid sensing pathways enhances expression of p21 and impairs hepatocyte cell cycle progression beyond the G1/S checkpoint leading to a marked impairment of liver regeneration after partial hepatectomy.