Crosstalk between liver sinusoidal endothelial cells and hepatocytes via IL-1α–IL1R1 axis exacerbates ischaemia/reperfusion injury in aged livers

Abstract

Background With population ageing, elderly patients account for a growing proportion of hepatic surgery recipients. Hepatic ischaemia-reperfusion injury (HIRI) is a major cause of postoperative liver dysfunction, particularly in aged livers, yet its mechanisms remain poorly understood. Objective We aimed to elucidate critical cellular interactions and molecular mechanisms underlying aggravated HIRI in aged livers to uncover therapeutic targets. Design Single-cell RNA sequencing and spatial transcriptomics were performed on liver tissues from humans, rats and mice across ages to define key cell types and intercellular signalling. HIRI and liver transplantation animal models, primary cell co-cultures and adeno-associated virus-mediated gene knockdown were used to prove cellular function and mechanisms. Neutralising antibody was used to assess therapeutic efficacy. Results Integrated analyses revealed a significant enrichment of senescent liver sinusoidal endothelial cells (LSECs) in aged livers, with the most prominent age-associated increase in crosstalk with hepatocytes, thereby promoting inflammation. Further investigation demonstrated increased transcriptional activity of myeloid ecotropic viral integration site 2 (MEIS2) in senescent LSECs, driving interleukin (IL)-1α expression via promoter binding and the IL-1α–IL1R1 axis subsequently activated NF-κB signalling in hepatocytes, enhancing inflammatory cytokine production. Interestingly, LSECs were also most strongly influenced by hepatocytes during liver ageing, as hepatocyte-derived TNF-α further enhanced MEIS2 transcriptional activity in LSECs, establishing a proinflammatory positive feedback loop. Furthermore, we confirmed that neutralising IL-1α effectively alleviated HIRI in aged livers. Conclusion Our findings identify the crosstalk between LSECs and hepatocytes in aged livers aggravating HIRI via MEIS2/IL-1α/IL1R1/TNF-α axis, suggesting that IL-1α neutralising antibody can be exploited as a promising therapeutic strategy for aged HIRI. Data are available upon reasonable request. The data sets analysed during the current study are available from the corresponding author on reasonable request. This study did not use any unique codes, and all analyses were performed in R and Python using standard protocols from previously published packages. All primers and other nucleic acid sequences are provided in the [online supplemental Table 1][1]. [1]: #DC16