Descrizione del progetto
L’infiammazione cronica localizzata potrebbe far luce su meccanismi condivisi da molte malattie
L’infiammazione cronica svolge un ruolo in numerose malattie e condizioni, tra cui cancro, malattie cardiache, diabete e artrite reumatoide. I processi di fondo sono strettamente correlati alla funzione del sistema immunitario. Anche le malattie granulomatose sono malattie infiammatorie croniche. Nonostante siano meno conosciute, esse interessano milioni di persone, spesso giovani. In tali malattie, i macrofagi del sistema immunitario si muovono incontrollati, portando a zone di infiammazione organizzata chiamate granulomi. È risaputo che i precursori dei macrofagi attivano la risposta del corpo a un danno del DNA (DNA Damage Response, DDR), conducendo a cambiamenti patologici nei macrofagi. Il progetto DDRMac, finanziato dall’UE, sta analizzando la possibilità che questi cambiamenti siano responsabili della formazione del granuloma. Visti i ruoli interconnessi dell’infiammazione, la DDR, la disfunzione del sistema immunitario, nonché numerose malattie e condizioni, i risultati potrebbero avere implicazioni terapeutiche di vasta portata.
Obiettivo
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.
Campo scientifico
Parole chiave
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Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
10117 Berlin
Germania