PhD Defense: Ronen Sumagin
ICAM-1 Distribution in the Microcirculation: Functional Consequences for Inflammatory Responses
Acute inflammation is characterized by an increase in the flux of solutes across the vessel wall and an increase in leukocyte transmigration. While it is widely assumed that inflammation is a characteristic of venular microcirculation, our data, supported by others, show that arterioles also serve an important role during inflammation. In the current study we show that one of the major differences between arterioles and venules is the expression levels and patterns of adhesion molecules, such as ICAM-1. The differences in the expression of adhesion molecules result in different leukocyte behavior. We show that while the levels of ICAM-1 significantly increase in both arterioles and venules following TNF treatment, the increase occurs in a fundamentally different way in these vessels. While in venules the increase in the expression of ICAM-1 following TNF occurs in endothelial cells (ECs) which basally expressed ICAM-1, in arterioles, which under normal conditions express significantly lower levels of ICAM-1 compared to venules, following TNF activation ICAM-1 expression in some ECs increased and in some decreased, regardless of the expression under basal conditions. Likewise we show that spatial variations in leukocyte-EC rolling interactions in arterioles and leukocyte adhesion interactions in venules correlate with the expression patterns of ICAM-1 expression on the endothelial surface. Importantly, we show that in different environments ICAM-1 can mediate different biological effects. While in venules it mainly mediates leukocyte adhesion and transmigration, in arterioles ICAM-1 has an explicit role in leukocyte rolling. Moreover, we show that the differences in phenotype between arteriolar and venular ECs, directly linked to downstream signaling that regulates vessel barrier function. Specifically, we show that ICAM-1serves as an important link between leukocyte-EC interactions and vessel permeability in both arterioles and venules. Engagement of ICAM-1 has been shown to trigger Ca2+ dependent cytoskeletal rearrangement in ECs, which are central to mechanisms underlying both leukocyte transmigration and the permeability responses. In the current work we identified a constitutive, ICAM-1 mediated and PKC dependent permeability (Ps) pathway in control (non-inflamed conditions) microvessels, and show that this switches to a Src dependent Ps pathway following TNF treatment. We also demonstrate that the interactions between ICAM-1 and its counter receptors on leukocytes ( 2-integrins) are essential for the increase in Ps levels during inflammation. Finally, this work highlights the important role arterioles play in inflammation by contributing to Ps changes, hence to tissue fluid and nutrient balance.