Decisions in metabolic inflammation of the liver: Adhesive interactions involved in leukocyte retention and resolution of inflammation in metabolic-inflammatory liver disease

Project Information

DEMETINL

Grant agreement ID: 683145

DOI

10.3030/683145

Project closed

EC signature date 9 June 2016

Start date 1 January 2017

End date 31 October 2022

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 953 250,00

EU contribution

€ 1 953 250,00

Coordinated by

TECHNISCHE UNIVERSITAET DRESDEN
Germany

Periodic Reporting for period 4 - DEMETINL (Decisions in metabolic inflammation of the liver: Adhesive interactions involved in leukocyte retention and resolution of inflammation in metabolic-inflammatory liver disease)

Reporting period: 2021-07-01 to 2022-10-31

Summary of the context and overall objectives of the project

Persistent inflammation is the common denominator and unifying mechanism of several common diseases, such as cardiometabolic disorders. Obesity-related metabolic-inflammatory conditions, including insulin resistance, diabetes and non-alcoholic fatty liver disease (NAFLD) lead to substantial morbidity and mortality and are therefore major health burdens in the western society, especially because obesity has evolved into a world epidemic. Inflammation has been recognized as an important player in the context of these diseases. Specifically, obesity-associated inflammation of metabolic organs, such as the adipose tissue or the liver, contributes to metabolic dysfunction and systemic inflammation, and thereby to progression of metabolic-inflammatory diseases. However, the mechanisms underlying inflammation of metabolic organs are not well understood. The major objective of this project is therefore to understand principles and mechanisms leading to sustained inflammation. A particular focus is inflammation of metabolic organs (adipose tissue and liver) in the context of obesity-related insulin resistance and inflammation, as well as NAFLD development and progression. Inflammation is triggered by tissue accumulation of innate immune cells, such as neutrophils and inflammatory monocytes/macrophages. Recruitment of these leukocytes is therefore a major mechanism that initiates inflammation. Whereas resolution of inflammation, involving several processes, including clearance of dead cells by macrophages, is functional in acute inflammation, resolution fails in chronic inflammatory conditions. In the latter case, failed resolution of inflammation is also linked with retention and sustained activation of innate immune cells in the tissue and contributes to perpetuation of inflammation and loss of tissue homeostasis. In other words, chronic inflammation is associated with persistent retention of inflammatory cells within the tissue, which may involve interactions of inflammatory cells with parenchymal cells, as well as dysfunctional resolution of inflammation. We therefore pursue the major objective of this project, which is to understand the mechanisms leading to sustained inflammation by (i) characterizing mechanisms for chronicity of inflammation particularly in the context of metabolic disease, including novel processes mediating inflammatory cell retention in metabolic organs and thus perpetuation of inflammation, and by (ii) studying resolution of inflammation in metabolic-inflammatory disease. In the latter approach, we also utilize models of acute inflammation, which is capable to resolve, in order to understand resolution principles.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Our project focuses on understanding mechanisms contributing to chronic inflammation. A particular focus is inflammation in metabolic organs, such as the adipose tissue and the liver in the context of metabolic-inflammatory disease, particularly obesity-related insulin resistance and metabolic syndrome as well as non-alcoholic fatty liver disease (NAFLD). Identifying those mechanisms is very important not only for understanding metabolic-inflammatory disease pathogenesis but also for identifying new specific therapeutic targets. We utilize experimental diet-induced obesity and NAFLD / non-alcoholic steatohepatitis (NASH) models. With regards to characterizing the mechanisms contributing to sustained inflammation and specifically processes mediating retention of inflammatory cells in metabolic organs in the context of metabolic-inflammatory disease, we identified a new pathway, by which the direct alpha4 integrin-dependent adhesion of inflammatory cells (especially macrophages) to parenchymal cells of the fat tissue mediates a self-sustained loop of metabolic organ inflammation and dysfunction. In addition, we studied further inflammatory mechanisms in NAFLD pathogenesis, including mechanisms of NAFLD-related fibrosis; we also studied immuno-metabolic mechanisms contributing to the process of trained innate immunity and the role of cellular metabolism on inflammatory cell activation. Moreover, we have studied the regulation of lipid metabolic homeostasis in the liver. With regards to mechanisms mediating resolution of inflammation, we have identified a new pathway promoting the clearance of dead cells by macrophages and thereby emergence of pro-resolving macrophages contributing to termination and clearance of inflammation.
Together, we performed a comprehensive immune-metabolic approach to identify novel pathogenesis principles in chronic inflammation particularly in the context of obesity-related metabolic inflammation.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The vast majority of the findings of the present project are beyond the state-of-the-art. This is also evidenced by multiple articles published in high-impact, prestigious journals. For instance, the discovery of a self-sustained loop of inflammation-driven metabolic organ dysfunction in obesity mediated by integrin-dependent macrophage adhesion and retention is a finding, which is clearly beyond the state-of-the-art and has important translational implications. Additionally, our studies on immunometabolic mechanisms involved in the process of innate immune training are beyond the state-of-the-art. Another example is the identification of a novel pathway mediating resolution of inflammation, which is beyond the state-of-the-art. Hence, our project has uncovered several new aspects pertinent to inflammation and metabolic-inflammatory pathology, which are beyond the state-of-the-art. We have identified important mechanisms, related to inflammatory or cell metabolic pathways, that are involved in sustained metabolic organ inflammation. Moreover, we have characterized novel pathways regulating metabolic homeostasis of the liver with important implications for NAFLD development and progression as well as further immunometabolic aspects of inflammatory cell activation. Our comprehensive analysis has contributed to improving our understanding of inflammatory processes and pathogenesis of metabolic inflammation.