Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.
J Immunol Res. 2021 Mar 29;2021:6670495. doi: 10.1155/2021/6670495. eCollection 2021.
At present, liver ischemia-reperfusion (IR) injury is still a great challenge for clinical liver partial resection and liver transplantation. The innate immunity regulated by liver macrophages orchestrates the cascade of IR inflammation and acts as a bridge. As a specific macrophage subunit of vacuolar ATPase, ATP6V0D2 (V-ATPase D2 subunit) has been shown to promote the formation of autophagolysosome in vitro. Our research fills a gap which has existed in the study of inflammatory stress about the V-ATPase subunit ATP6V0D2 in liver macrophages. We first found that the expression of specific ATP6V0D2 in liver macrophages was upregulated with the induction of inflammatory cascade after liver IR surgery, and knockdown of ATP6V0D2 resulted in increased secretion of proinflammatory factors and chemokines, which enhanced activation of NLRP3 and aggravation of liver injury. Further studies found that the exacerbated activation of NLRP3 was related to the autophagic flux regulated by ATP6V0D2. Knocking down ATP6V0D2 impaired the formation of autophagolysosome and aggravated liver IR injury through nonspecific V-ATPase activation independent of V-ATPase-Notchl-Hesl signal axis. In general, we illustrated that the expression of ATP6V0D2 in liver macrophages was upregulated after liver IR, and by gradually promoting the formation of autophagolysosomes to increase autophagy flux to limit the activation of liver inflammation, this regulation is independent of the Notch1-Hes1 signal axis.
目前，肝脏缺血再灌注（IR）损伤仍然是临床肝部分切除和肝移植的一大挑战。肝脏巨噬细胞调节的固有免疫协调了 IR 炎症的级联反应，并起到了桥梁作用。作为液泡型 ATP 酶的特定巨噬细胞亚基，ATP6V0D2（V-ATPase D2 亚基）已被证明能促进体外自噬溶酶体的形成。我们的研究填补了肝脏巨噬细胞中 V-ATPase 亚基 ATP6V0D2 在炎症应激方面研究的空白。我们首次发现，在肝 IR 手术后，炎症级联诱导后肝巨噬细胞中特定的 ATP6V0D2 表达上调，敲低 ATP6V0D2 导致促炎因子和趋化因子的分泌增加，从而增强 NLRP3 的激活和肝损伤的加重。进一步的研究发现，NLRP3 的加剧激活与 ATP6V0D2 调节的自噬流有关。敲低 ATP6V0D2 通过非特异性 V-ATPase 激活而不依赖于 V-ATPase-Notchl-Hesl 信号轴损害自噬溶酶体的形成，加重肝 IR 损伤。总的来说，我们说明了肝巨噬细胞中 ATP6V0D2 的表达在肝 IR 后上调，并通过逐渐促进自噬溶酶体的形成来增加自噬流，从而限制肝脏炎症的激活，这种调节独立于 Notch1-Hes1 信号轴。
