Project description
Localised chronic inflammation could shed light on shared mechanisms across many diseases
Chronic inflammation plays a role in numerous diseases and conditions, among them cancer, heart diseases, diabetes and rheumatoid arthritis. The processes underlying it are closely related to immune system function. Granulomatous diseases are also chronic inflammatory diseases. Although less well known, they affect millions, often young people. In these diseases, macrophages of the immune system run amok, leading to areas of organised inflammation called granulomas. It is known that macrophage precursors trigger the body's DNA damage response (DDR), leading to pathological changes in macrophages. The EU-funded DDRMac project is investigating the possibility that these changes are responsible for granuloma formation. Given the interlinked roles of inflammation, DDR, immune system dysfunction, and numerous diseases and conditions, the outcomes could have far-reaching therapeutic implications.
Objective
Macrophage differentiation programs are critical for the outcome of immunity against infection, chronic inflammatory diseases and cancer. How diverse inflammatory signals are translated to macrophage programs in the large range of human pathologies is largely unexplored. In the last years we focused on macrophage differentiation in granulomatous diseases. These affect millions worldwide, including young adults and children and tend to run a chronic course, with a high socioeconomic burden. Their common hallmark is the formation of granulomas, macrophage-driven structures of organized inflammation that replace healthy tissue. We revealed that macrophage precursors in granulomas experience a replication block and trigger the DNA Damage Response (DDR), a fundamental cellular process activated in response to genotoxic stress. This leads to the formation of multinucleated macrophages with tissue-remodelling signatures (Herrtwich, Cell 2016). Our work unravelled an intriguing link between genotoxic stress and granuloma-specific macrophage programs. The molecular pathways regulating DDR-driven macrophage differentiation and their role in chronic inflammatory pathologies remain however a black box. We hypothesize that the DDR promotes macrophage reprogramming to inflammation-maintaining modules. Such programs operate in granulomatous diseases and in chronic arthritis. Using state-of-the art genetic models, human tissues and an array of techniques crossing the fields of immunology, cell biology and cancer biology, our goal is to unravel the macrophage-specific response to genotoxic stress as an essential regulator of chronic inflammation-induced pathologies. The anticipated results will provide the scientific community with new knowledge on the role of genotoxic stress in immune dysregulation and will carry tremendous implications for the therapeutic targeting of macrophages in the context of chronic inflammatory diseases and cancer.
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Funding Scheme
ERC-STG - Starting GrantHost institution
10117 Berlin
Germany