AUTHOR=Kusakabe Jiro , Hata Koichiro , Tajima Tetsuya , Miyauchi Hidetaka , Zhao Xiangdong , Kageyama Shoichi , Tsuruyama Tatsuaki , Hatano Etsuro 

TITLE=Properdin inhibition ameliorates hepatic ischemia/reperfusion injury without interfering with liver regeneration in mice

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1174243

DOI=10.3389/fimmu.2023.1174243

ISSN=1664-3224

ABSTRACT=<p>Hepatic ischemia/reperfusion injury (IRI) often causes serious complications in liver surgeries, including transplantation. Complement activation seems to be involved in hepatic IRI; however, no complement-targeted intervention has been clinically applied. We investigated the therapeutic potential of Properdin-targeted complement regulation in hepatic IRI. Male wild-type mice (B10D2/nSn) were exposed to 90-minute partial hepatic IRI to the left and median lobes with either monoclonal anti-Properdin-antibody (Ab) or control-immunoglobulin (IgG) administration. Since the complement system is closely involved in liver regeneration, the influence of anti-Properdin-Ab on liver regeneration was also evaluated in a mouse model of 70% partial hepatectomy. Anti-Properdin-Ab significantly reduced serum transaminases and histopathological damages at 2 and 6 hours after reperfusion (<italic>P &lt;</italic>0.001, respectively). These improvements at 2 hours was accompanied by significant reductions in CD41+ platelet aggregation (<italic>P</italic> =0.010) and ssDNA+ cells (<italic>P &lt;</italic>0.001), indicating significant amelioration in hepatic microcirculation and apoptosis, respectively. Characteristically, F4/80+ cells representing macrophages, mainly Kupffer cells, were maintained by anti-Properdin-Ab (<italic>P &lt;</italic>0.001). Western blot showed decreased phosphorylation of only Erk1/2 among MAPKs (<italic>P</italic> =0.004). After 6 hours of reperfusion, anti-Properdin-Ab significantly attenuated the release of HMGB-1, which provokes the release of proinflammatory cytokines/chemokines (<italic>P</italic> =0.002). Infiltration of CD11b+ and Ly6-G+ cells, representing infiltrating macrophages and neutrophils, respectively, were significantly alleviated by anti-Properdin-Ab (both <italic>P &lt;</italic>0.001). Notably, anti-Properdin-Ab did not affect remnant liver weight and BrdU+ cells at 48 hours after 70% partial hepatectomy (<italic>P</italic> =0.13 and 0.31, respectively). In conclusion, Properdin inhibition significantly ameliorates hepatic IRI without interfering with liver regeneration.</p>