Inhibiting ATP6V0D2 Aggravates Liver Ischemia-Reperfusion Injury by Promoting NLRP3 Activation via Impairing Autophagic Flux Independent of Notch1/Hes1

Author:

Wang Ziyi123,Wang Hao123,Chen Xuejiao123,Han Sheng123,Zhu Yulin4,Wang Hanhua5,Cheng Feng123ORCID,Pu Liyong123ORCID

Affiliation:

1. Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

2. Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China

3. NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China

4. Department of Cardiothoracic Surgery, Affiliated Yancheng Clinical School of Nanjing Medical University, China

5. Department of Radiation Oncology, Affiliated Yancheng Clinical School of Nanjing Medical University, China

Abstract

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.

Publisher

Hindawi Limited

Subject

Immunology,General Medicine,Immunology and Allergy

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