IL-34 Inhibits Acute Rejection of Rat Liver Transplantation by Inducing Kupffer Cell M2 Polarization

Background Recent studies have demonstrated that IL-34 is implicated in the regulation of macrophage functions. However, the effect of IL-34 on Kupffer cells (KCs) in acute rejection (AR) of liver transplantation remains unclear. Methods IL-34 expression was detected in graft and serum from allotransplantation and syngeneic transplantation groups. The adeno-associated virus expressing IL-34 (AAV-IL-34) was used to assess the effect of IL-34 on AR of rat liver transplantation. The effect of IL-34 on KC polarization was evaluated by in vitro and in vivo assays. KCs in donors were depleted by clodronate treatment before transplantation, and the nontreated KCs or LPS-treated KCs were transferred into recipients during liver transplantation. Results IL-34 expression levels in grafts and serum were decreased in the allotransplantation group compared to the syngeneic transplantation group. AAV-IL-34 treatment induced KC M2 polarization in vivo and inhibited the AR of rat liver transplantation. Moreover, we found that IL-34 switched the phenotype of KCs from M1 to M2 by activating the PI3K/Akt pathway in vitro. In addition, the results of KC deletion and adoptive transfer experiments showed that the AR inhibition induced by IL-34 was M2 KC-dependent. Conclusions IL-34 plays an important role in KC M2 polarization-dependent AR inhibition of rat liver transplantation. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. * These authors contributed equally to this work Corresponding author Zhongjun Wu, M.D., Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. wzjtcy@126.com Authorship Z.W. and Z.Z. participated in designing experiments and editing the final draft of the article. Z.Z., G.P., C.T., Z.L., D.Z. and X.W. participated in performing the studies. Z.Z. and G.P. participated in analyzing the data. Disclosure The authors declare no conflicts of interest. Funding This work was supported by the National Science Foundation of China, (No. 81672959), the Natural Science Foundation of Chongqing, China (No. cstc2015shmszx120019). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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