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Crosstalk of Metabolism and Inflammation

Periodic Reporting for period 4 - CMIL (Crosstalk of Metabolism and Inflammation)

Période du rapport: 2020-10-01 au 2021-09-30

Inflammation is a response to noxious stimuli and initiates tissue repair. If resolution fails, however, chronic inflammation develops, which drives tissue damage in many diseases including autoimmunity, cancer and infections. Inflammatory processes are increasingly being appreciated as tightly integrated with metabolic pathways. The molecular crosstalk occurs on different levels including secreted metabolites and cytokines. We hypothesized that this interface of metabolism and inflammation represents a functional rheostat that shapes tissue damage and disease. In this project we analysed the metabolic and inflammatory processes in models of inflammatory diseases such as viral infections and investigated how inflammatory processes affect the metabolism of the host and vice versa. We took a systemic perspective on the entire organism and organ-level changes and initially focused on the liver as the central organ for metabolism and a hotspot for receiving, processing and distributing local and systemic signals. Cutting-edge technologies including sequencing, quantitative proteomics and metabolomics were used to generate longitudinal multi-dimensional maps of virus-induced alterations. Paired with immunological, virological and pathological analyses, we identified novel disease-relevant nodes that bridge metabolism and inflammation (e.g. DOI: 10.1016/j.immuni.2019.10.014 DOI: 10.1371/journal.ppat.1008973 DOI: 10.1038/s41590-019-0397-y). In addition, we aimed to conceptually advance the field of systemic immunometabolism and shed light onto the interplay of immunology and the metabolic disease cachexia in the context of infections and cancer (DOI: 10.1016/j.immuni.2020.08.012 DOI: 10.1038/s41577-021-00624-w). In summary, our interdisciplinary approach pushed the boundaries of our knowledge about the crosstalk of metabolism and inflammation and provided new mechanistic and conceptual insights into how our immune system works.
We performed extensive multi-dimensional profiling of changes on the host side during viral-infection and uncovered a novel role for how the antiviral cytokine type I interferon orchestrates the metabolic reprogramming of the liver (DOI: 10.1016/j.immuni.2019.10.014). More specifically, we could delineate how the central metabolic pathway of the urea cycle is perturbed during infection and how this feed backs onto antiviral T cell responses. This work has brought new attention to hepatocytes as key regulatory cells of the immune response. Moreover, we dissected additional metabolic pathways in the liver such as the tryptophane-kynurenine pathway and established paradigms for how infections induce changes in systemic immunometabolism (DOI: 10.1371/journal.ppat.1008973). We In also described a novel role for the lipid-sensing receptor TREM2 and how it modulates hepatitis during viral infection (DOI: 10.1038/s41598-017-10637-y).
Further to investigating infection-associated changes in the liver, we became interested into systemic immunometabolic changes and took a particular focus on adipose and muscle tissue. In diseases such as cancer, chronic inflammation and infection, wide-spread metabolic and inflammatory alterations are found and associated with the devastating disease cachexia. This is manifested as body weight loss, reduction of fat and lean body mass, lack of appetite, lethargy amongst other symptoms, which cannot be reversed by nutritional interventions. Currently, there’s an incomplete understanding of the underlying mechanisms and standard therapies are lacking. We uncovered a previously unrecognized role by our T cell responses mediate cachexia during viral infection and established a novel model to study infection-associated cachexia (Baazim et al. 2019, DOI: 10.1038/s41590-019-0397-y). We discussed its implication and broader context of how the field of immunology can both deliver and benefit from studying this important disease of cachexia in a review (Baazim et al. 2021, DOI: 10.1038/s41577-021-00624-w).
In this project we aimed for a better understanding of metabolism and inflammation and the identification of novel genes and pathways that confer tissue protection and/or improve control of otherwise chronic viruses. This research journey led us to unexpected insights into infection-associated changes in organs such as adipose and muscle tissue that are not necessarily in the focus of immunologists. Our expansion from a liver-centric focus to other body compartments allowed us to break new grounds by developing a more integrated perspective on how to integrate organ pathophysiology with immunology and infection biology. Our work provided new fundamental insights into how viruses shape our organism and systemic metabolism, thereby offering new entry points for future studies of tissue biology and cross-organ communication. During this project we established an interdisciplinary framework to assess systemic immunometabolism in homeostasis and during viral infections. This encompasses the use of experimentally well-defined infection models and the integrative use of transcriptional, metabolic, imaging and bioinformatic readouts from different organ compartments and time points. We reviewed the conceptual foundation and highlighted important future questions (Systemic Immunometabolism: Challenges and Opportunities; DOI: 10.1016/j.immuni.2020.08.012). Together, we are convinced that our work provided innovative aspects to better grasp and dissect complex diseases such as infections or cancer. Thereby, we hope to have prepared the grounds for new advancements into therapeutic treatments of inflammatory diseases.