Human α1-antitrypsin attenuates injury-induced Inflammation through interacting with high mobility group box-1 (HMGB1)

• Published in: The Journal of immunology (1950) Vol. 198; no. 1_Supplement; pp. 82 - 82.31
• Main Authors: Ohayon, David E, Schuster, Ronen, Mizrahi, Mark I, Lior, Yotam, Baranovski, Boris M, Shahaf, Galit, Lewis, Eli C
• Format: Journal Article
• Language: English
• Published: 01-05-2017
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.198.Supp.82.31

HMGB1 is involved in pathologies such as cellular injury and autoimmunity. Indeed, upon binding to immune-related receptors, HMGB1 promotes an inflammatory response, such as that might take part in pancreatic islet destruction during both autoimmune diabetes and islet transplant rejection. Specifically, elevated circulating HMGB1 levels were reported in patients with type 1 diabetes, and increased release of HMGB1 was found to correlate with injury degree and islet allograft survival. The anti-inflammatory and immune-modulatory acute-phase protein human α1-antitrypsin (hAAT) promotes islet survival in both transplantation and autoimmune diabetes models. While AAT binds to damage-released proteins, such as gp96 and HSP70, its tissue protective mechanism remains poorly understood. We now extend this observation that AAT protective activity is related to its interaction with HMGB1. Clinical-grade AAT (Glassia, Kamada Ltd., Israel), diminished recombinant HMGB1-induced inflammatory responses in mouse pancreatic islets (while restoring disrupted insulin inflammation-mediated release). Similar behavior was depicted in HMGB1-stimulated peritoneal macrophages introduced to hAAT. In addition, hAAT modulated HMGB1-inducible surface expression by altering its distribution. Lastly, we show by immunoprecipitation that HMGB1 associated proteins was positive for the presence of AAT, this is also supported by a direct ELISA. Our findings suggest that hAAT is a naturally-occurring regulator of inflammatory responses mediated by extracellular HMGB1, such that preclude outcomes of islet transplantation. hAAT may therefore be considered for therapy of cell damage-mediated pathologies in a clinically-safe manner.