肝脏巨噬细胞活化在非酒精性脂肪性肝炎(NASH)发生发展中起着重要作用。本项目在前期实验中发现：在小鼠肝脏中有89%的巨噬细胞为DPP-4阳性巨噬细胞，且NASH小鼠肝脏DPP-4阳性的炎性M1巨噬细胞含量上调，DPP-4阳性的抗炎性M2巨噬细胞含量下调，而抑制DPP-4活性能调控巨噬细胞M1/M2极性并改善NASH炎症相关症状。本项目拟进一步研究DPP-4影响NASH进程的作用及分子机制。本项目将在细胞水平研究DPP-4阳性巨噬细胞极性在NASH进程中的作用；并利用DPP-4靶点之一MIP-1α敲除的小鼠，在体内研究DPP-4调控M1/M2巨噬细胞极性影响NASH进程的作用机制；同时探讨MIP-1α受体CCR1/CCR5拮抗剂作为治疗NASH药物候选的潜在可能性。该研究有助于我们了解在巨噬细胞M1/M2极化过程中DPP-4的调控作用及其分子机制，为NASH的治疗提供理论基础和分子手段。

The activation of Kupffer cells (KCs) was confirmed to play a central role in the development of NASH. Our previous studies demonstrated that: 89% macrophages are DPP-4 positive macrophages in liver. Furthermore, DPP-4 positive classically activated macrophage (M1 macrophages) were significantly increased in NASH mice, while DPP-4 positive alternatively activated macrophage (M2 macrophages) were decreased, when compared with the normal mice. Meanwhile, inhibition of DPP-4 activity regulated macrophage polarization and ameliorated NASH in mice. In this study, primary KCs and bone marrow derived macrophages will be used to examine the role of DPP-4 positive macrophages on the pathogenesis of NASH. Furthermore, MIP-1α (one of the DPP-4 substrates) deficiency mice will be used to investigate the role and the mechanism of DPP-4 on the pathogenesis of NASH via regulating macrophage polarization. Finally, the effect of MIP-1α receptor CCR1/CCR5 antagonist on NASH progression will be evaluated as the potential candidate therapeutic drugs. In summary, we will clarify the role and mechanism of DPP-4 in the pathogenesis of NASH by regulating macrophages polarization, which may contribute to the better understanding and more scientific approaches for the prevention and treatment of NASH.