Origin and function of the endogenous danger signal HMGB1 in the inflammatory response following infectious and immunological liver injury.

• Applicant: Dr. Peter Hübener
• Subject Area: Gastroenterology ; Immunology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 266597033

Inflammation is an integral component of most liver diseases and contributes to organ damage. While the roles of distinct cytokines and chemokines in the regulation of hepatic inflammation are well established, it is unclear how these inflammatory responses are intiated. It is generally assumed that stressed or damaged cells can release cellular components that trigger inflammation through evolutionarily conserved receptor systems, and are thus termed damage associated molecular patterns. By contrast, molecular constituents of pathogens, such as lipopolysaccharide, are believed to trigger inflammation in the setting of infection, and are thus called pathogen associated molecular patterns. This conceptual distinction between sterile and infectious inflammation, however, is being replaced by a concept in which parenchymal cells, inflammatory cells and, where applicable, pathogens enter a complex interplay of dynamic reciprocal interactions. The role of endogenous danger signals in the regulation of these interactions is subject of a growing scientific interest. The ubiquitously expressed nucleoprotein HMGB1 is released by necrotic cells and can also be secreted by activated inflammatory cells. Through interactions with its receptors RAGE, TLR2 and TLR4 on inflammatory cells, it is believed to exert proinflammatory effects, however, clean genetic ablation studies have been precluded by the early postnatal lethality of global Hmgb1 knockout animals. In previous investigations on mice carrying conditional Hmgb1 ablation, we could demonstrate that the protein can be efficiently removed from various tissues of the adult organism without affecting cellular homeostasis or function, but that it is essential for the initiation of an inflammatory response following sterile tissue damage. Here, we seek to test the hypothesis that suppressed inflammation in the absence of HMGB1 precludes an efficient immunological host response to infectious and immunological liver damage. To this end, we aim to first identify the main cellular source of HMGB1 in mouse models of bacterial and viral infection as well as immunological liver damage. Next, we will delete the gene specifically from hepatocytes, endothelial cells or leukocytes and study the respective effects on the immunological response to the aforementioned injury models. Further investigations aim to identify relevant HMGB1 receptors as well as differential effects of HMGB1 on parenchymal and inflammatory cell populations involved in this response. Finally, the possibility of pharmacological interventions aimed at HMGB1 and its receptors will be addressed as well as the applicability of differentially acetylated HMGB1 forms and naturally occuring HMGB1 autoantibodies in patient sera as diagnostic and prognostic tools in the management of infectious and immunological liver diseases.

• DFG Programme: Research Grants