THBS1 Acts as an Intracellular "Brake" to Orchestrate Immune Remodeling and Mitigate Post-transplantation Liver Injury

Background: The immune microenvironment following liver transplantation (LT) is characterized by a precarious balance between acute inflammation and tissue repair. Identifying the molecular switches that drive this immunological transition is crucial for improving graft survival. This study investigated the role of Thrombospondin-1 (THBS1) as a central regulator of macrophage functional plasticity during hepatic injury and recovery.
Methods: Through cross-species and multi-model transcriptomic integration, we identified a conserved macrophage subpopulation governing the resolution of liver inflammation. We employed myeloid-specific Thbs1 knockout mice and various liver injury models (IRI, toxic injury and chronic injury) to evaluate its systemic impact. Molecular mechanisms were elucidated using chromatin immunoprecipitation (ChIP), Co-IP, and loss-of-function assays in primary macrophages.
Results: Single-cell profiling identified THBS1 as a hallmark of a transitional macrophage subset that emerges during the peak of hepatic inflammation. Acting as an immunological brake, THBS1 is induced during the inflammatory peak to counteract pro-inflammatory signaling (S100A8/A9) and steer the functional transition toward a Trem2+ pro-repair phenotype.

In vivo, myeloid-specific knockdown of THBS1 failed to attenuate the inflammatory response, leading to significantly increased hepatocyte necrosis and a reduction in pro-repair signaling. Mechanistically, THBS1 counterbalances the pro-inflammatory environment. It promotes the TGF-β-Smad2/3 signaling axis, which in turn inhibits NF-κB activity. This negative feedback loop ensures the timely transition of macrophages towards a Trem2-positive reparative phenotype, thereby preventing persistent tissue damage.

Conclusion: Our study defines THBS1 as a critical rheostat of macrophage-mediated inflammation. By suppressing NF-κB through the Smad2/3 pathway, THBS1 orchestrates the "immune remodeling" necessary for liver repair. Targeting the THBS1/Smad2/3 axis offers a therapeutic window to prevent excessive post-transplant injury and promote graft homeostasis.