Spatial proteomics and cell-cell cross-talk analysis reveal PD-L1 and IL-6 interaction in human primary sclerosing cholangitis

ABSTRACTBackground pIn vitro, aPBMCs induced the upregulation of 68 immunoregulatory genes in BECs; PD-L1 and IL-6 up-regulation was confirmed at protein level. In turn, BECs determined an increased apoptosis in T (CD4+/CD8+) and NK cells. In co-culture, the exposure of BECs to IL-6/sIL-6r complex induced significant PD-L1 up-regulation (12.7±1.3; pConclusions These findings define a critical immunosuppressive axis in PSC driven by BEC-derived IL-6 and PD-L1. Mechanistically, we identified IL-6 as an upstream regulator of PD-L1 via JAK/STAT3 and NF-κB pathways, predominantly through IL-6 trans-signalling. Our study provides a rationale for targeting epithelial-immune cell interactions as a therapeutic strategy in PSC. IMPACT AND IMPLICATIONS Pathogenetic basis of primary sclerosing cholangitis (PSC) is poorly understood, hampering the development of specific therapeutic approaches. We individuated IL-6 as a key upstream regulator of PD-L1 via the JAK/STAT3 and NF-κB pathways in biliary epithelial cells, representing a major player in regulating epithelial-immune cross-talk during biliary injury. The individuation of PD-L1 pathway in immune-epithelial cell interactions in PSC may be of help in the understanding of this disease, as well as in defining treatment strategies.