Expression of Concern: The haptoglobin beta subunit sequesters HMGB1 toxicity in sterile and infectious inflammation

• Published in: Journal of internal medicine Vol. 282; no. 1; pp. 76 - 93
• Main Authors: Yang, H., Wang, H., Wang, Y., Addorisio, M., Li, J., Postiglione, M. J., Chavan, S. S., Al‐Abed, Y., Antoine, D. J., Andersson, U., Tracey, K. J.
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell Publishing Ltd 01.07.2017
• Subjects: Acetaminophen; acetaminophen intoxication; Analgesics; Animal models; Binding; CD163; CD163 antigen; Cecum; cytokine; Functional analysis; Haptoglobin; haptoglobin (β); Heme; Heme oxygenase (decyclizing); Hemoglobin; HMGB1; HMGB1 protein; Infectious diseases; Inflammatory diseases; Interleukin 10; Liver; Oxygenase; Peritonitis; Proteins; Rodents; Sepsis; Structure-function relationships; Surgery; Toxicity
• ISSN: 0954-6820; 1365-2796
• DOI: 10.1111/joim.12619

Background Extra‐corpuscular haemoglobin is an endogenous factor enhancing inflammatory tissue damage, a process counteracted by the haemoglobin‐binding plasma protein haptoglobin composed of alpha and beta subunits connected by disulfide bridges. Recent studies established that haptoglobin also binds and sequesters another pro‐inflammatory mediator, HMGB1, via triggering CD163 receptor‐mediated anti‐inflammatory responses involving heme oxygenase‐1 expression and IL‐10 release. The molecular mechanism underlying haptoglobin–HMGB1 interaction remains poorly elucidated. Methods Haptoglobin β subunits were tested for HMGB1‐binding properties, as well as efficacy in animal models of sterile liver injury (induced by intraperitoneal acetaminophen administration) or infectious peritonitis (induced by cecal ligation and puncture, CLP, surgery) using wild‐type (C57BL/6) or haptoglobin gene‐deficient mice. Results Structural–functional analysis demonstrated that the haptoglobin β subunit recapitulates the HMGB1‐binding properties of full‐length haptoglobin. Similar to HMGB1–haptoglobin complexes, the HMGB1–haptoglobin β complexes also elicited anti‐inflammatory effects via CD163‐mediated IL‐10 release and heme oxygenase‐1 expression. Treatment with haptoglobin β protein conferred significant protection in mouse models of polymicrobial sepsis as well as acetaminophen‐induced liver injury, two HMGB1‐dependent inflammatory conditions. Conclusions Haptoglobin β protein offers a novel therapeutic approach to fight against various inflammatory diseases caused by excessive HMGB1 release. This Expression of Concern relates to the article “The haptoglobin beta subunit sequesters HMGB1 toxicity in sterile and infectious inflammation” by Yang, Wang, Wang, Addorisio, Li, Postiglione, Chavan, Al‐Abed, Antoine, Andersson & Tracey (DOI: 10.1111/joim.12906).