LEUKOMIGREG

Regulation of expression and function of integrin alpha6beta1 during leukocyte migration

 Partecipanti

Mappa

 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

 Obiettivo del progetto (Objective)

'Leukocyte migration through blood vessels and directional migration in the extravascular tissue towards sites of infection and/or injury are fundamental components of the organism’s immune response. Their inappropriate occurrence is also an important contributing factor to the development of many inflammatory conditions such as stroke and atherosclerosis. Many details of the associated mechanisms remain unclear in particular the role(s) of leukocyte interactions with extracellular matrix proteins. Of relevance, studies from the host lab have shown that neutrophils upregulate their principal laminin receptor, integrin alpha6beta1 in order to migrate through the vascular basement membrane during extravasation. The aims of my project will be to build on these novel findings through investigations that address the molecular mechanisms involved in alpha6beta1 upregulation and studies into the functional role of this integrin in monocyte migration through venular walls and in interstitial migration of monocytes and neutrophils. These objectives will be studied through the use of in vitro and in vivo models. Specifically, leukocyte expression of alpha6 will be analysed during transmigration in vivo by fluorescence microscopy. The molecular mechanisms leading to alpha6 upregulation will be examined with a series of in vitro experiments and leukocyte migration through the vessel wall and in the interstitium will be explored using intravital microscopy incorporating advanced imaging techniques established in the host laboratory. The obtained results will advance our understanding of the mechanisms that leukocytes employ to migrate towards inflammatory sites and will help to identify potential new targets for development of novel clinical interventions for inflammatory conditions. Additionally, the models and assays that I will develop during the progression of the study will be invaluable for future investigations of trafficking of myeloid cells.'

Introduzione (Teaser)

Inflammation is a critical factor contributing to the development of various diseases such as myocardial infarction, stroke, rheumatoid arthritis and atherosclerosis. Understanding this process at the molecular level especially with respect to the migration of immune cells was the subject of a European study.

Descrizione progetto (Article)

The direction-dependent migration of immune cells such as neutrophils to sites of infection or injury is of central importance in maintaining innate immunity. However, in rare cases, neutrophils have been observed to travel back from the injury site to the vessel, a phenomenon referred to as reverse transmigration.

The EU-funded 'Regulation of expression and function of integrin alpha6beta1 during leukocyte migration' (LEUKOMIGREG) project set out to delineate the molecular mechanisms underlying this process.

Researchers discovered that the immune cells that reverse transmigrate from the site of infection or injury undergo a stimulus-dependent phenotypical change. Neutrophils capable of transmigration expressed high levels of the adhesion molecule ICAM-1 and reactive oxygen species.

Importantly, they observed that during inflammation the transendothelial migration of neutrophils gets disrupted due to lower expression of junctional adhesion molecule C. Interestingly, the reverse transmigration of neutrophils was more prominent and could account for the spread of inflammation in cases such as ischaemia-reperfusion injury.

Overall, the work by the LEUKOMIGREG provided new knowledge on the role of neutrophil phenotypes in inflammation and immunity. The identified molecules could serve as targets for dampening the inflammatory state of various conditions and possibly alleviating many symptoms for faster recovery.