Siglec-15 promotes M2 polarization of Kupffer cells via DAP12/IRAK-M axis to alleviate acute rejection in liver transplantation.

BACKGROUND: Acute rejection (AR) remains a significant issue affecting the efficacy of liver transplantation, and the Kupffer cell (KC) phenotype is crucial for AR. Recent studies have indicated that Siglec-15 can regulate macrophage polarization. However, the role of Siglec-15 in liver transplantation remains unclear. METHODS: Immune tolerance (BN-BN) and immune rejection (Lewis-BN) models were developed in rats to assess the expression of Siglec-15 in KCs. Clinical specimens were also collected for further validation. Then, in vitro experiments were conducted to explore the function and specific mechanisms of Siglec-15 in regulating KC polarization. Finally, Siglec-15 was overexpressed in rats to evaluate its impact on AR. RESULTS: Compared to the immune tolerance group, the expression of Siglec-15 in KCs was lower in the immune rejection group. Similarly, Siglec-15 levels were significantly decreased in patients with AR, and Siglec-15 expression levels were significantly negatively correlated with AR severity. KCs were isolated from the liver tissue of healthy BN rats and treated with lipopolysaccharide, and overexpressing Siglec-15 promoted M2 polarization of KCs. Mechanistically, the GENEMANIA website predicted that the DNAX-activation protein 12 (DAP12)/interleukin-1 receptor-associated kinase-M (IRAK-M) pathway serves as a potential downstream target of Siglec-15. Molecular docking and in vitro experiments confirmed this result. Further silencing either DAP12 or IRAK-M via siRNA abolished the promoting effect of Siglec-15 on the M2 polarization of KCs. Furthermore, overexpressing Siglec-15 reduced AR and improved survival rates in rats. CONCLUSIONS: Siglec-15 induces M2 polarization of KCs through the DAP12/IRAK-M axis, thereby alleviating AR during liver transplantation. Siglec-15 is a potential effective target for therapeutic intervention in AR.