Inhibition of macrophage activation by TRIM47

The immune system is critical to protect us from infections by the numerous pathogens we encounter on a daily basis. In particular, specialized immune cells present at major surfaces where our bodies are exposed to the environment are critical in this aspect. One of the major classes of immune cells residing at the exposed surfaces are macrophages. These cells are on the one hand critical for direct protection during microbial infection, but on the other hand also essential regulators of other immune cell types. Although it is important that the anti-microbial response is properly activated during infection, it is equally essential that this response is inhibited after clearance of infection to prevent hyper- inflammation and auto-immunity. Likewise, it is critical to prevent activation of resting immune cells in the absence of pathogens. However, how the immune response is constraint at the molecular level to achieve this, remains poorly understood. We recently identified a member of the tripartite motif protein family, which limited the inflammatory response in macrophages. In the context of this grant we will determine how this factor limits the immune response at the molecular level, which will aid in determining its relevance for preventing auto-immune disease and hyper-inflammation. Together, the proposed work will expand our understanding of how the inflammatory response is inhibited during resting conditions, and during physiological resolution of infection, how deregulation of these responses contribute to auto-immune diseases, and ultimately how to better diagnose immune disorders and design intervention strategies.

The immune system is critical to protect us from infections by the numerous pathogens we encounter on a daily basis. In particular, specialized immune cells present at major surfaces where our bodies are exposed to the environment are critical in this aspect. One of the major classes of immune cells residing at the exposed surfaces are macrophages. These cells are on the one hand critical for direct protection during microbial infection, but on the other hand also essential regulators of other immune cell types. Although it is important that the anti-microbial response is properly activated during infection, it is equally essential that this response is inhibited after clearance of infection to prevent hyper-inflammation and auto-immunity. Failure to do so properly can result in auto-immune pathologies. In this study, we set out to identify new regulators that work in shutting off the inflammatory response. Using a state-of-the-art technique to manipulate the presence of each individual human functional protein in cells, we discovered several novel factors that determine the abundance of two central cellular regulators of macrophage activation and shut-off. One of the identified factors is essential to making a macrophage activator in the first place after exposure to danger-signals released from infected cells, whereas the other is key to degradation of the same macrophage activator once an infection has been cleared. In our experiments we found that the factor that degrades the macrophage activator has binding sites that facilitate their interaction, thereby subsequently tagging the macrophage activator with a degradation signal. This event marks it for destruction by a designated cellular protein degradation machine. The second discovered regulator is essential to making the macrophage activator in the first place during infection. While the different components of this activation pathway were thought to be known, we identified a novel factor that upon experimental deletion, prevented macrophage activation. In our study, we demonstrated that this regulator rather specifically regulates the production of many immune products, but only few non-immune factors. The newly identified regulator is made in humans, but also in organisms without immune system. This suggests, that this discovered factor may have acquired new immune-regulatory functions in humans. Follow-up studies enabled by the results of this project will focus in part on unraveling exactly how this newly discovered player drives the production of macrophage activators. Taken together, this study has provided a wealth of new insight into how immune cells are shut-off to prevent auto-immunity. Two hitherto unknown factors that control this process were identified and characterized. These results enable future work to understand at a molecular level how these factors work together to ensure proper immune shut-off, at the right time.