RhIL-11 reverses liver damage in septic mice by STAT3-mediated M-MDSCs induction modulated by a parallel mTORC1 signaling branch

Hyperinflammatory response in early stage of sepsis was the key factor leading to multi-organ injury. Therefore, exploring an effective therapy to attenuate or reverse hyperinflammation was the priority of sepsis treatment. Previous study from our team showed that recombinant human interleukin-11 (rhIL-11) was a promising anti-inflammation cytokine in sepsis. However, the molecular mechanism was not fully elucidated. This study aims to evaluate the therapeutic potential of rhIL-11 in septic mice model and explore the underlying the molecular mechanism. A cecal ligation and puncture (CLP) model was applied to induce septic mice. Mice were separated into five groups with six animals in each group, including normal, sham, sham + rhIL-11, CLP and CLP + rhIL-11 groups. Therapeutic potential of rhIL-11 was evaluated by comparing body weight, survival time and liver damage (hematoxylin and eosin (H&E) staining, pro-inflammatory cytokines and serum measurements of liver enzymes). Hepatic myeloid-derived suppressor cells (MDSC) percentage was also compared. In vitro, MDSC differentiation from bone marrow (BM) cells was induced in the presence of appropriate stimuli, followed by the proportion and subsets analysis via flow cytometer. The related signal pathways including STAT3 and mTORC1 were detected by western blotting. The effect of MDSCs inhibition by STAT3 and mTORC1 inhibitors on septic mice was evaluated by comparing survival time, liver damage and MDSCs percentage. Here, we declared that early treatment of rhIL-11 exerted a liver protective effect and caused the expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) in septic mice model. The results of in vitro studies declared that rhIL-11 promoted differentiation of BM cells into M-MDSCs phenotypically and functionally via activating STAT3 signaling, which was cross-regulated by the mTORC1. Furthermore, we also elucidated that mTORC1 bound directly to STAT3 through an interaction between raptor and TOS motif in STAT3. Finally, inhibition of mTORC1 or STAT3 in vivo blocked the differentiation of M-MDSCs and attenuated liver protective effect of rhIL-11. Taken together, these results suggested that early treatment of rhIL-11 in septic mice might reverse the hepatic damage at least in part by inducing the differentiation of M-MDSCs via STAT3 signaling pathway, and STAT3 signaling is modulated by a parallel branch of mTORC1.