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<p>Succinate regulates inflammation through its receptor, succinate receptor 1 (SUCNR1). However, the effects of this interaction on Kupffer cell (KC)-driven inflammation during liver ischemia–reperfusion injury (IRI) remain unclear. Herein, we investigated the succinate/SUCNR1 axis in the progression of liver IRI. In this study, succinate levels and SUCNR1 expression were analyzed in mice underwent segmental liver IRI. <i>Sucnr1</i> deficiency (<i>Sucnr1</i><sup>−/−</sup>) and Wild-type mice were treated with or without clodronate before liver IRI modeling, and a co-culture system was established to assess the impact of <i>Sucnr1</i> deficiency in KCs on hepatocyte viability and apoptosis. KC activation status and polarization were determined, in vivo and in vitro<i>.</i> Furthermore, the downstream pathways in regulating KC polarization were investigated. We observed a significant increase in succinate levels in the serum and liver, and SUCNR1 expression in KCs after IRI. <i>Sucnr1</i> deletion alleviated liver IRI and hepatocyte apoptosis either in vivo or in vitro. However, the aforementioned hepatoprotective effects were abolished by the depletion of KCs with clodronate. <i>Sucnr1</i> deletion inhibited KC activation and M1 polarization, and dampened proinflammatory cytokine release after liver IRI. In addition, <i>Sucnr1</i> knockout reversed the increasing phosphorylation of ERK and NF-κB p65 in KCs following liver IRI. The phosphorylation of ERK/NF-κB p65 and M1 polarization in KCs were also inhibited by the SUCNR1 antagonist Compound 4C or ERK inhibitor SCH772984. Together, these findings suggest that SUCNR1 deficiency protects against liver IRI by modulating KC activation and polarization probably through the ERK/NF-κB pathway.</p> Graphical Abstract <p></p>

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SUCNR1 Deficiency Alleviates Liver Ischemia–Reperfusion Injury by Regulating Kupffer Cell Activation and Polarization Through the ERK/NF-κB Pathway in Mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月19日

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  • Huan Yang,
  • An Wei,
  • Xinting Zhou,
  • Zhiwei Chen,
  • Yiheng Wang

摘要

Succinate regulates inflammation through its receptor, succinate receptor 1 (SUCNR1). However, the effects of this interaction on Kupffer cell (KC)-driven inflammation during liver ischemia–reperfusion injury (IRI) remain unclear. Herein, we investigated the succinate/SUCNR1 axis in the progression of liver IRI. In this study, succinate levels and SUCNR1 expression were analyzed in mice underwent segmental liver IRI. Sucnr1 deficiency (Sucnr1−/−) and Wild-type mice were treated with or without clodronate before liver IRI modeling, and a co-culture system was established to assess the impact of Sucnr1 deficiency in KCs on hepatocyte viability and apoptosis. KC activation status and polarization were determined, in vivo and in vitro. Furthermore, the downstream pathways in regulating KC polarization were investigated. We observed a significant increase in succinate levels in the serum and liver, and SUCNR1 expression in KCs after IRI. Sucnr1 deletion alleviated liver IRI and hepatocyte apoptosis either in vivo or in vitro. However, the aforementioned hepatoprotective effects were abolished by the depletion of KCs with clodronate. Sucnr1 deletion inhibited KC activation and M1 polarization, and dampened proinflammatory cytokine release after liver IRI. In addition, Sucnr1 knockout reversed the increasing phosphorylation of ERK and NF-κB p65 in KCs following liver IRI. The phosphorylation of ERK/NF-κB p65 and M1 polarization in KCs were also inhibited by the SUCNR1 antagonist Compound 4C or ERK inhibitor SCH772984. Together, these findings suggest that SUCNR1 deficiency protects against liver IRI by modulating KC activation and polarization probably through the ERK/NF-κB pathway.

Graphical Abstract