Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - DEMETINL (Decisions in metabolic inflammation of the liver: Adhesive interactions involved in leukocyte retention and resolution of inflammation in metabolic-inflammatory liver disease)

Teaser

Persistent inflammation is the common denominator and unifying mechanism of several common diseases, such as cardiometabolic diseases. Obesity-related metabolic-inflammatory conditions, including insulin resistance (IR), diabetes and non-alcoholic fatty liver disease (NAFLD)...

Summary

Persistent inflammation is the common denominator and unifying mechanism of several common diseases, such as cardiometabolic diseases. Obesity-related metabolic-inflammatory conditions, including insulin resistance (IR), 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 thereby to metabolic-inflammatory disease development and progression. However, the mechanisms underlying inflammation of metabolic organs are not well understood. The major objective of this project is therefore to understand the mechanisms leading to sustained inflammation of metabolic organs (adipose tissue and especially the liver) in the context of obesity-related IR development and NAFLD development. Inflammation is triggered by accumulation of innate immune cells, such as neutrophils and inflammatory monocyte/macrophages. Recruitment of these leukocytes is therefore a major mechanism that initiates inflammation. Whereas resolution of inflammation, involving several processes, including clearance of dead inflammatory 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 with dysfunctional resolution of inflammation. We therefore pursue the major objective of this project (which is to understand the mechanisms leading to sustained metabolic inflammation) by (i) characterizing, in the context of metabolic disease, mechanisms for chronicity of inflammation, 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 and apply them to non-resolving metabolic-inflammatory disease.

Work performed

Our project focuses on understanding mechanisms contributing to chronification of metabolic inflammation, especially inflammation in metabolic organs, such as the adipose tissue and the liver in the context of metabolic-inflammatory disease, particularly obesity-related insulin resistance (IR) and 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, for instance, 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-integrin-dependent adhesion of inflammatory cells to parenchymal cells mediates a self-sustained loop of metabolic organ inflammation and dysfunction. In addition, we study further inflammatory mechanisms in NAFLD pathogenesis, including further adhesion receptors and receptors of the complement system, mechanisms of NAFLD-related fibrosis, immuno-metabolic mechanisms contributing to the process of trained innate immunity, the effect of cellular metabolism (with a special focus on lipid metabolism) on inflammatory cell activation that may regulate inflammation and homeostasis of metabolic organs, especially of the liver. With regards to mechanisms mediating resolution of inflammation, we have identified a new pathway promoting the emergence of pro-resolving macrophages and thereby termination and clearance of inflammation. These aspects are also assessed in the context of metabolic-inflammatory disease.

Together, we perform a comprehensive immune-metabolic approach to identify novel pathogenesis principles in chronic inflammation particularly in the context of obesity-related metabolic disorders, like IR and NAFLD.

Final results

The majority of the findings of the present project so far are beyond the state-of-the-art. This is also evidenced by 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. In the second part of the project, we will complete the analysis of additional potential mechanisms involved in metabolic inflammation or regulating its resolution. We anticipate to identify and verify additional players and mechanisms, mediated by adhesive and/or inflammatory pathways, involved in sustained metabolic organ inflammation, NAFLD development and progression, pathways regulating metabolic homeostasis of the liver and further immunometabolic aspects of inflammatory cell activation. We believe that, upon completion, our project will have contributed to improving our understanding of inflammatory processes and pathogenesis of metabolic inflammation.