AUTHOR=Liu Yanyao , Pu Xingyu , Qin Xiaoyan , Gong Junhua , Huang Zuotian , Luo Yunhai , Mou Tong , Zhou Baoyong , Shen Ai , Wu Zhongjun 

TITLE=Neutrophil Extracellular Traps Regulate HMGB1 Translocation and Kupffer Cell M1 Polarization During Acute Liver Transplantation Rejection

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.823511

DOI=10.3389/fimmu.2022.823511

ISSN=1664-3224

ABSTRACT=Neutrophil extracellular traps (NETs) play vital functions during hepatic ischemic reperfusion injury (IRI) as well as acute rejection (AR) induced immune responses to inflammation. After liver transplantation, HMGB1, an inflammatory mediator, participates in pathophysiological processes of AR. Even though studies have found that HMGB1 can promote NETs formation, the correlation between NETs and HMGB1 in AR following liver transplantation has not been elucidated. In this study, serum NETs levels were significantly elevated in patients after liver transplantation and the circulating levels of NETs was negative correlated with liver function. Operation of liver transplantation and elevated level of extracellular HMGB1 promotes NETs formation. HMGB1/TLR-4/MAPK signaling pathway activation, which is initiated by HMGB1, plays a role in NETs processes. Moreover, in the liver, the Kupffer cells were found to be the major HMGB1 secretory cells. NETs mediated Kupffer cells M1 polarization and HMGB1 intracellular translocation were dramatically decreased by DNase-1 inhibition. Additionally, combination treatment using TAK-242 (a TLR-4 inhibitor) and rapamycin exerted better anti-damage efficacies when compared to either treatment alone, implying that combined therapy may be a potential therapy for AR following liver transplantation.