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

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

doi:10.3389/fimmu.2023.1174243

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

Front Immunol. 2023 Aug 16:14:1174243. doi: 10.3389/fimmu.2023.1174243. eCollection 2023.

Authors

Jiro Kusakabe¹, Koichiro Hata¹, Tetsuya Tajima¹, Hidetaka Miyauchi¹, Xiangdong Zhao¹, Shoichi Kageyama¹, Tatsuaki Tsuruyama², Etsuro Hatano¹

Affiliations

¹ Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
² Center for Anatomical, Pathological, and Forensic Medical Research, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Abstract

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 (P <0.001, respectively). These improvements at 2 hours was accompanied by significant reductions in CD41+ platelet aggregation (P =0.010) and ssDNA+ cells (P <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 (P <0.001). Western blot showed decreased phosphorylation of only Erk1/2 among MAPKs (P =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 (P =0.002). Infiltration of CD11b+ and Ly6-G+ cells, representing infiltrating macrophages and neutrophils, respectively, were significantly alleviated by anti-Properdin-Ab (both P <0.001). Notably, anti-Properdin-Ab did not affect remnant liver weight and BrdU+ cells at 48 hours after 70% partial hepatectomy (P =0.13 and 0.31, respectively). In conclusion, Properdin inhibition significantly ameliorates hepatic IRI without interfering with liver regeneration.

Keywords: alternative pathway; complement; hepatectomy; hepatic ischemia/reperfusion injury; liver transplantation; properdin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Ischemia
Liver
Liver Regeneration
Male
Mice
Properdin*
Reperfusion Injury* / prevention & control

Substances

Properdin

Grants and funding

This study was supported by a research grant program from the Japanese Association for Complement Research and the Medical Research and Development Programs Focused on Technology Transfer, Development of Advanced Measurement and Analysis Systems (SENTAN) from the Japan Agency for Medical Research and Development, AMED (No. 21hm0102063h0004).