Periodic Reporting for period 3 - DDRMac (DNA Damage Response-instructed Macrophage Differentiation in Granulomatous Diseases)
Okres sprawozdawczy: 2022-04-01 do 2023-09-30
The goal of DDRMac is to elucidate how macrophages' response to genotoxic stress may promote chronic inflammation-induced pathologies. To do this, we interrogate the role of genotoxic stress and the DNA Damage Response (the signalling pathway by which cells in our body respond to genotoxic stress) in the context of granuloma formation in vivo but also in the context of osteoclast formation in vitro. The latter is particularly relevant for diseases in which osteoclasts (the multinucleated macrophages that 'eat' bone) destroy tissue, such as in rheumatoid arthritis. The anticipated results will provide the scientific community with new knowledge on the role of genotoxic stress in shaping our immune responses and will carry significant implications for the therapeutic targeting of macrophages in chronic inflammatory diseases and cancer.
In vivo we have analysed the role of the DNA damage response in depth using models in which granuloma macrophages differentiate without infectious stimuli, including a model of Crohn's disease and a model of lung inflammation - reminiscent of sarcoidosis.
Finally, during the COVID-19 pandemic, we have performed significant work to elucidate the mechanisms of autoimmune organ damage in the context of chronically elevated type I interferons or severe viral infection. This work has revealed that innate tissue resident lymphocytes communicate with tissue macrophages, changing the program of the latter, to promote epithelial proliferation and a pro-fibrotic response. This link of innate immunity and tissue damage may explain the differential susceptibility of individual hosts to autoimmune disease, suggesting a model where activation of innate immunity, such as occurring in a severe viral infection, leads to organ damage via a cellular axis that includes tissue resident lymphocytes, reprogrammed disease associated macrophages and epithelial cells.