Final Report Summary - LEUKOMIGREG (Regulation of expression and function of integrin alpha6beta1 during leukocyte migration)
Background
Leukocyte migration through blood vessels and their directional migration in the extravascular tissue towards sites of infection and/or injury are fundamental components of the organism’s immune response. However, inappropriate occurrence of these events can be an important contributing factor to the development of acute and chronic inflammatory conditions such as myocardial infarction, stroke, rheumatoid arthritis and atherosclerosis. These are leading causes of long-term illness and death in the western world and thus form a considerable social and economic burden. The unarguable involvement of leukocyte migration in the pathogenesis of such destructive inflammatory conditions has led to much investigations and progress in our understanding of the associated cellular and molecular mechanisms but there remain many unanswered questions.
Objectives
The aim of this project was to address certain aspects of leukocyte migration through blood vessels and their directional migration in the extravascular tissue towards sites of infection or injury. Specifically, we analysed the role of integrin alpha6beta1 during monocyte migration through venular walls. Furthermore we extended our initial objectives to include the analysis of reverse transmigration of neutrophils. This phenomenon, where transmigrated neutrophils migrate back from the subendothelial space into the vessel lumen, was demonstrated by our group in vivo for the first time. In order to further elucidate the physiological and pathological implications of this process we analysed the phenotype of reverse transmigrated neutrophils.
Results
As proposed the phenotype of transmigrated leukocytes, particularly expression of integrin alpha6beta1, was analysed in the peritonitis model and revealed that classical monocytes exhibit significant changes in phenotype post transmigration that can be stimulus-specific. We are planning to submit this part of the work as an independent publication. Although these experiments showed many interesting changes in both monocyte and neutrophil phenotypes post transmigration, no regulation of the integrin alpha6 subunit was observed under the employed conditions.
Therefore we modified our original plan and followed up an exciting new route that emerged during the phenotype analysis phase of the project and analysed leukocyte phenotypes upon in vivo reverse transmigration of neutrophils. We were able to show that this phenomenon is correlated with the occurrence of a neutrophil subset expressing high levels of the adhesion molecule ICAM-1 and reactive oxygen species. These cells in turn are correlated with the extent of lung inflammation. These observations led to a high-impact publication (Woodfin, Voisin, Beyrau et al., Nature Immunology, 2011). Subsequently we extended these findings to examine the phenotype and roles of this newly identified neutrophil subset in more detail and we are currently preparing the findings of this study for publication with the fellow as first author. Furthermore, this work has led to the publication of a detailed review on the role of neutrophil phenotypes in inflammation and immunity (Beyrau et al., Open Biology, 2012).
Leukocyte migration through blood vessels and their directional migration in the extravascular tissue towards sites of infection and/or injury are fundamental components of the organism’s immune response. However, inappropriate occurrence of these events can be an important contributing factor to the development of acute and chronic inflammatory conditions such as myocardial infarction, stroke, rheumatoid arthritis and atherosclerosis. These are leading causes of long-term illness and death in the western world and thus form a considerable social and economic burden. The unarguable involvement of leukocyte migration in the pathogenesis of such destructive inflammatory conditions has led to much investigations and progress in our understanding of the associated cellular and molecular mechanisms but there remain many unanswered questions.
Objectives
The aim of this project was to address certain aspects of leukocyte migration through blood vessels and their directional migration in the extravascular tissue towards sites of infection or injury. Specifically, we analysed the role of integrin alpha6beta1 during monocyte migration through venular walls. Furthermore we extended our initial objectives to include the analysis of reverse transmigration of neutrophils. This phenomenon, where transmigrated neutrophils migrate back from the subendothelial space into the vessel lumen, was demonstrated by our group in vivo for the first time. In order to further elucidate the physiological and pathological implications of this process we analysed the phenotype of reverse transmigrated neutrophils.
Results
As proposed the phenotype of transmigrated leukocytes, particularly expression of integrin alpha6beta1, was analysed in the peritonitis model and revealed that classical monocytes exhibit significant changes in phenotype post transmigration that can be stimulus-specific. We are planning to submit this part of the work as an independent publication. Although these experiments showed many interesting changes in both monocyte and neutrophil phenotypes post transmigration, no regulation of the integrin alpha6 subunit was observed under the employed conditions.
Therefore we modified our original plan and followed up an exciting new route that emerged during the phenotype analysis phase of the project and analysed leukocyte phenotypes upon in vivo reverse transmigration of neutrophils. We were able to show that this phenomenon is correlated with the occurrence of a neutrophil subset expressing high levels of the adhesion molecule ICAM-1 and reactive oxygen species. These cells in turn are correlated with the extent of lung inflammation. These observations led to a high-impact publication (Woodfin, Voisin, Beyrau et al., Nature Immunology, 2011). Subsequently we extended these findings to examine the phenotype and roles of this newly identified neutrophil subset in more detail and we are currently preparing the findings of this study for publication with the fellow as first author. Furthermore, this work has led to the publication of a detailed review on the role of neutrophil phenotypes in inflammation and immunity (Beyrau et al., Open Biology, 2012).