ERC Starting Grant: DDRMac

ERC Grants

Granulomas are a typical histological finding of several chronic inflammatory diseases. They develop as a reaction to a persistent inflammatory stimulus and consist of macrophages that differentiate into multinucleated giant cells and epithelial cells. These structures of organised inflammation replace healthy tissue causing organ dysfunction.

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. We hypothesize that the DDR promotes macrophage reprogramming to inflammation-maintaining modules. Our goal is to unravel the macrophage-specific response to genotoxic stress as an essential regulator of chronic inflammation-induced pathologies such as sarcoidosis, inflammatory bowel diseases and rheumatoid arthritis. We postulate that the interruption of signalling cascades leading to granuloma formation may be a new therapeutic strategy for chronic inflammatory diseases.