Recombinant Chitinase 3-like 1 Alleviates Liver Transplantation-induced Cold Ischemia/Reperfusion Injury by Promoting M2 Polarization of Kupffer Cells.

Background: Hepatic cold ischemia/reperfusion injury (IRI) significantly restricts graft utilization and adversely affects the prognosis of liver transplantation recipients. The overactivation of Kupffer cells (KCs) is recognized as a significant cellular response in hepatic IRI. This study aimed to investigate the potential of recombinant chitinase 3-like 1 (rCHI3L1) to regulate M2 polarization of KCs and alleviate hepatic cold IRI.

Methods: The differentially expressed genes in hepatic cold IRI were investigated using human liver and serum samples from liver transplantation patients. A rat hepatic cold IRI model was established and treated with adeno-associated virus 9-shChi3l1 and rCHI3L1 to evaluate changes in the degree of liver injury, inflammatory response, and the M2 polarization of KCs. Western blot, immunofluorescence, flow cytometry, RNA sequencing, and coimmunoprecipitation were used to explore the potential role of rCHI3L1 in primary KCs.

Results: CHI3L1 was upregulated in human and rat donor livers after cold IRI, with KCs as the primary source. rCHI3L1 treatment alleviated hepatic IRI, as evidenced by lower serum alanine aminotransferase and aspartate aminotransferase levels, along with limited liver damage and apoptosis, whereas adeno-associated virus 9-shChi3l1 treatment exacerbated it. Mechanistically, rCHI3L1 promoted the M2 polarization of KCs by activating Janus kinase 1/signal transducer and activator of transcription 3 via interleukin 13 receptor α 2, thereby alleviating hepatic damage and apoptosis.

Conclusions: rCHI3L1 alleviated rat hepatic cold IRI by inducing KCs M2 polarization via activating the Janus kinase 1/signal transducer and activator of transcription 3 axis, potentially providing a research basis for treating clinical hepatic IRI.