Periodic Reporting for period 3 - DDRMac (DNA Damage Response-instructed Macrophage Differentiation in Granulomatous Diseases)
Berichtszeitraum: 2022-04-01 bis 2023-09-30
Macrophages are critical for the outcome of immunity against infection, chronic inflammatory diseases and cancer. Macrophages in chronic inflammation change their program and function giving rise to disease-associated macrophage states. How diverse inflammatory signals instruct macrophage programs is largely unexplored. DDRMac aims to elucidate pathways that instruct the differentiation of granuloma macrophages, specialized types of macrophages that are characteristic of granulomatous diseases. Granulomatous diseases 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. Granulomas replace healthy tissue thus causing organ dysfunction.
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.
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.
So far, we have uncovered an essential role of the DNA damage response in the formation of multinucleated macrophages. Using genetic models, we have found that DNA damage is increased before the formation of multinucleated cells and the response to DNA damage is required for the formation of multinucleated cells. These findings have been supported by several methodologies, including high content image cytometry and live cell imaging.
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.
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.
Our data are entirely novel, since the role of genotoxic stress in macrophage differentiation is largely unknown. Also the nature of the cellular crosstalk that explains how activated innate immunity causes immune complex mediated organ damage was previously a black box. In the remaining time of this project we will explore in depth the mechanistic underpinnings by which macrophages integrate genotoxic stress signalling to reprogram themselves in chronic granulomatous microenvironment, and the role of this process in disease progression and inflammatory pathology.