XBP1s repression regulates Kupffer cell polarization leading to immune suppressive effects protecting liver allograft in rats.

• Acute rejection response is still the leading cause of liver graft loss and failure. • We uncovered an immune regulatory role of X-box binding protein 1 (XBP1) on the immune function of Kupffer cells (KCs) which influence the immune response after liver transplantation. • XBP1s protected rat's liver allograft via JAK-STAT mediated KCs polarization. Polarized kupffer cells (KCs) influence the immune response after liver transplantation. We report an undiscovered immune regulatory role of X-box binding protein 1 (XBP1) on immune function of kupffer cells (KCs). Acute rejection model using rats. We found that suppression of XBP1s in lipopolysaccharide (LPS) -activated KCs could increase the expression of arginase-1 (Arg-1) and CD204 but also decrease the expression levels of MHC-II and CD40 and shift the phenotype markers of KCs toward M2 via the janus kinase (JAK) 3- Signal Transducer And Activator Of Transcription (STAT) 6 pathway, presenting an immunosuppressive function by enhancing anti-inflammatory cytokine secretion and accelerating apoptosis of activated T cells. XBP1s over-expression in KCs shift the phenotype markers on KCs towards M1 via the JAK1-STAT1 pathway and have shown a strong pro-inflammatory property. Down-regulation of XBP1s in KCs changed the phenotype and cytokine secretion profile towards M2 and markedly protected the function and structure of allograft liver, prolonging the recipient's survival compared with control and normal saline groups in rats. Our findings reveal a novel regulatory mechanism of XBP1 in an induced immuno-suppressive state to protect rat's liver allograft via JAK-STAT mediated KCs polarization. [ABSTRACT FROM AUTHOR]