A specific subset of macrophages—immune cells that patrol the abdominal cavity—uses a surface receptor called ACKR3 to direct other immune cells to sites of infection and then help calm the inflammation once the threat is gone. Peritonitis, a severe infection of the abdominal lining, can be life-threatening if the immune response is either too weak (allowing bacteria to spread) or too strong (causing tissue damage). Researchers know that macrophages are central to this process, but the molecular signals that guide their movement and coordination with other immune cells—such as neutrophils and B cells—remain poorly understood. This project aims to fill that gap by focusing on ACKR3, a receptor that controls chemokine gradients—the chemical trails that immune cells follow. This is fundamental science. If successful, it will reveal how a specific macrophage population orchestrates the immune response in the peritoneal cavity. In the longer term, the proportion of ACKR3-positive macrophages could serve as a biomarker to predict which patients are at risk of severe peritonitis. A drug that boosts these cells might one day improve immune recruitment and clearance of infection, but that application is years away. For now, the work clarifies a basic mechanism of immune cell choreography during inflammation.
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Background The peritoneal cavity is a space that surrounds the abdominal organs and is primarily protected by a group of immune cells known as macrophages. Macrophages become activated and eliminate pathogens when an infection occurs within the peritoneal cavity. They migrate to the site of inflammation, engulf pathogens, and regulate immune responses, providing the initial defence against infections. However, the precise mechanisms by which macrophages efficiently migrate to the site of inflammation and cooperate with other immune cells, such as B cells and neutrophils, to control inflammation remain unclear. Recent studies suggest that macrophages play an important role in this process, but the molecular mechanisms governing their function, dynamics, and regulation are still not fully understood. Furthermore, after the infection is cleared, the mechanisms by which macrophages resolve the immune response and restore the peritoneal cavity to a healthy state remain unclear. Objective of the Study The objective of this study is to investigate the function and role of a subset of atypical chemokine receptor 3 (ACKR3)-expressing peritoneal macrophages in the peritoneal cavity. ACKR3 is known to regulate chemokines, molecules that control the migration (chemotaxis) of immune cells to sites of inflammation. However, the specific role of ACKR3 in peritoneal macrophages remains unclear. In this study, I hypothesise that ACKR3-positive peritoneal macrophages play a key role in appropriately directing immune cells to the site of infection or inflammation and in regulating immune responses during these processes. Research Methods To test this hypothesis, I will use mouse models of inflammation and employ cutting-edge technologies such as single-cell RNA sequencing, genetically modified mice, and live-cell imaging. These techniques will allow me to precisely track the behaviour of ACKR3-positive macrophages at the cellular level and comprehensively understand their dynamics and function. The study will focus on the following points: The differentiation, developmental process, and functional characteristics of ACKR3-positive macrophages. The effects of ACKR3 deficiency in macrophages on the behaviour of peritoneal immune cells and their impact on inflammatory responses and pathology. Real-time tracking of the impact of ACKR3 on immune cell dynamics and interactions during peritonitis. Potential Applications and Benefits This research will demonstrate that ACKR3 is a useful marker for identifying a subset of effector macrophages. Further studies could indicate the potential of the proportion of ACKR3-positive macrophages as a biomarker for predicting the risk of severe peritonitis in patients. Furthermore, the future development of a drug that promotes the differentiation of ACKR3-positive macrophages in the peritoneal cavity could potentially lead to improvements in the treatment of peritonitis by efficiently promoting the recruitment of immune cells to inflammation sites and enhancing immune defences in the peritoneal cavity.
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