Disulfide-HMGB1 signals through TLR4 and TLR9 to induce inflammatory macrophages capable of innate-adaptive crosstalk in human liver transplantation

作者：Allyson Q. Terry, Hidenobu Kojima, Rebecca A. Sosa, Fady M. Kaldas, Jackson L. Chin, Ying Zheng, Bita V. Naini, Daisuke Noguchi, Jessica Nevarez‐Mejia, Yiping Jin, Ronald W. Busuttil, Aaron S. Meyer, David W. Gjertson, Jerzy W. Kupiec‐Weglinski, Elaine F. Reed · 发表于：American Journal of Transplantation · 年份：2023 · DOI：10.1016/j.ajt.2023.08.002 · 被引用次数：35 · 研究领域：Advanced Glycation End Products research、Organ Transplantation Techniques and Outcomes、Adenosine and Purinergic Signaling

Ischemia-reperfusion injury (IRI) during orthotopic liver transplantation (OLT) contributes to graft rejection and poor clinical outcomes. The disulfide form of high mobility group box 1 (diS-HMGB1), an intracellular protein released during OLT-IRI, induces pro-inflammatory macrophages. How diS-HMGB1 differentiates human monocytes into macrophages capable of activating adaptive immunity remains unknown. We investigated if diS-HMGB1 binds toll-like receptor (TLR) 4 and TLR9 to differentiate monocytes into pro-inflammatory macrophages that activate adaptive immunity and promote graft injury and dysfunction. Assessment of 106 clinical liver tissue and longitudinal blood samples revealed that OLT recipients were more likely to experience IRI and graft dysfunction with increased diS-HMGB1 released during reperfusion. Increased diS-HMGB1 concentration also correlated with TLR4/TLR9 activation, polarization of monocytes into pro-inflammatory macrophages, and production of anti-donor antibodies. In vitro, healthy volunteer monocytes stimulated with purified diS-HMGB1 had increased inflammatory cytokine secretion, antigen presentation machinery, and reactive oxygen species production. TLR4 inhibition primarily impeded cytokine/chemokine and costimulatory molecule programs, whereas TLR9 inhibition decreased HLA-DR and reactive oxygen species production. diS-HMGB1-polarized macrophages also showed increased capacity to present antigens and activate T memory cells. In murine OLT, diS-HMG...