Neutrophils—a type of white blood cell—are squeezing through blood vessel walls in the wrong direction, and this may be spreading inflammation to other organs. Inflammation is the body’s defence against infection, but when it goes wrong it drives diseases from arthritis to vasculitis. For 15 years, researchers have known which molecules help immune cells cross blood vessel walls, but they have not watched how these cells actually move in living tissue. Using a 3D real-time imaging platform, the team recently observed neutrophils reversing direction as they cross venular walls in models of vascular injury. This reverse migration was linked to inflammation developing in a second organ, suggesting that disrupted transmigration may actively spread disease. This project will track neutrophil behaviour in real time across several inflammatory models—endotoxemia, ischemia-reperfusion injury, and small-vessel vasculitis—to map how often reverse migration occurs, whether it increases with age, and what molecular mechanisms drive it. The work is fundamental science: it aims to reveal a previously unknown route by which inflammation disseminates through the body. If successful, it could reframe how researchers think about inflammatory disease progression and identify new targets for therapies that block the spread of inflammation, rather than just treating its local symptoms.
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Inflammation is a vital immune response mounted to protect the host against infection but can also be the underlying cause of numerous pathologies. A key component of inflammation is migration of leukocytes through venular walls, a phase of leukocyte trafficking that I have been investigating for ~15 years. Whilst we now know much about the molecular players that support this event, little is known about the mode and dynamics of leukocyte transmigration in vivo. Using an advanced 3D real-time im aging platform we have recently noted the occurrence of disrupted modes of neutrophil transmigration including neutrophil reverse transmigration in models of vascular injury. Importantly, the latter was associated with development of second organ inflammation, radically indicating that disrupted modes of leukocyte transmigration may impact disease progression and dissemination. These findings highlight the need for more rigorous analysis of leukocyte transmigration and form the basis of the proposed research. Key goals: - To unravel the profiles and dynamics (eg duration, directionality) of neutrophil interactions with components of the venular wall in real-time in vivo using both physiological and pathological inflammatory models (eg endotoxemia, ischemia-reperfusion injury, small-vessel vasculitis). - To investigate the pathogenic impact of disrupted modes of neutrophil transmigration (eg neutrophil reverse transmigration) and the prevelance of such responses with increased age. - The above will be consolidated to dissect the mechanisms of disrupted transmigration events and their associated pathogenecity. Collectively using innovative imaging modalities the proposed research will unravel new concepts and thus provide a step-change to the field of inflammation.
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