To explore how macrophages responses to genotoxic stress may rewire their genetic programs and change their functions, we interrogated the role of the DNA Damage Response, or DDR in macrophages. Using genetic models to target DDR-related molecules specifically in macrophages, we analysed the role of the DDR in macrophages of multiple tissues, including the lung, intestine, joints, bone and liver, both in health and during the development of inflammatory diseases, such as intestinal or joint inflammation.
Our work revealed that the DDR was important for the differentiation and function of tissue macrophages both in health and during inflammation, but not all tissue macrophages were equal in their dependence on the DDR for their function. The conceptual framework of these studies was published in two articles (Kasapi A, Triantafyllopoulou A. Genotoxic stress signalling as a driver of macrophage diversity. Cell Stress 2022 Feb 14;6(3):30-44. and Fabry LAR, Triantafyllopoulou A. Der Rolle der DNA-Schadensantwort bei granulomatösen Erkrankungen [The role of the response to DNA damage in granulomatous diseases]. Z Rheumatol. 2022 Dec;81(10):881-887).
In addition to our investigation of granulomatous inflammatory diseases, we explored the pathways that control macrophage differentiation and function in autoimmune diseases, such as systemic lupus erythematosus (SLE). Around five million people worldwide, mostly young women, are affected by SLE, which can lead to kidney inflammation (lupus nephritis). Lupus nephritis is in many patients difficult to treat and can lead to kidney failure and thus dialysis.In SLE, endogenous DNA damage can lead to the release of damage-associated molecular patterns leading to chronic stimulation of our immune system by endogenous nucleic acids. This leads to the development of autoantibodies against self nucleic acids. Macrophages sense both nucleic acids and bind autoantibodies, leading to their activation. Activated macrophages fuel inflammation and tissue damage.We uncovered that a small, specialized group of tissue resident immune cells—known as innate lymphoid cells (ILCs) is activated in lupus via their surface receptor NKp46 and directly programs macrophages that are coming into the tissue from the bone marrow. This triggers an avalanche of effects that leads to lupus nephritis and subsequent severe tissue damage. Depleting NKp46-expressing ILC suppressed tissue damage.
To explore how ILC controlled macrophages we used single-cell RNA sequencing of the entire kidney as well as immune cells. scRNA-seq is a technique that allows to analyze in depth the program of individual cells and to explore their potential interactions. We found out that when NKp46 is activated, ILC increase their production of the protein GM-CSF, a growth factor that expands proinflammatory macrophages, causing severe tissue damage and the formation of scar tissue, known as fibrosis. Blocking the NKp46 receptor with antibodies or genetically deleting the receptor, suppressed kidney damage. A similar anti-inflammatory effect was observed when GM-CSF was blocked. These findings showed how a small population of innate lymphoid cells that reside in tissues, can sense stress induced by endogenous DNA damage and amplify inflammation by controlling proinflammatory macrophages. This work was published in the journal Nature (Biniaris-Georgallis SI, Aschman T, Stergioula K et al. Amplification of autoimmune organ damage by NKp46-activated ILC1. Nature 2024) and communicated to the public via a press release and an newspaper article (joint press release from the Charite and the MDC ‘Surprising mechanism of lupus kidney damage identified’, August 14, 2024. Interview by Adelheid Müller-Lissner titled ‘Immune disease Lupus: scientists from Berlin want to stop the self-destruction of the kidney’ was published online on the Tagespiegel, August 28, 2024).
