The role of glycoprotein 130 in homing
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Citation
Abstract
Coordinated lymphocyte adhesion and migration is a hallmark of the adaptive immune response in both physiological and pathological conditions. Therefore, understanding the mechanisms underlying lymphocyte trafficking at the molecular level may provide novel targets for the treatment of immune-mediated diseases. The controlled migratory pattern of lymphocytes, commonly referred to as homing, is critically dependent on specialized microvasculature and is facilitated by the expression of adhesion molecules and signaling chemokines. During steady state conditions, homing of immune cells occurs continuously in the lymph nodes due to the constitutive expression of homing molecules, whereas during an inflammatory condition, a reactive up regulation of these adhesion molecules is necessary for immune cell trafficking to take place.
The dynamics of immune cell recruitment, demonstrated by intravital microscopy, showed that lymphocyte adhesion in the target tissue's microvascular bed is mostly restricted to the post-capillary and collecting venules, whereas arterioles and capillaries can not support this interaction. High shear stress exerted by fluid dynamics in the lumen of venules requires intravascular lymphocytes to anchor using receptor molecules that form mechanically stable bonds with counter receptors in the vascular wall (von Andrian & Mackay, 2000). These molecules play a key role in lymphocyte binding and facilitate the directed migration of lymphocytes by functioning as a tissue specific recognition molecule differentially expressed on the surface of lymph node ECs (von Andrian & Mackay, 2000). Specialized venular ECs found in lymph nodes and Peyer's Patches (PPs) called high endothelial venules (HEVs) constitutively express on their surface a specialized type of this homing molecule called addressins, allowing for the continuous recruitment of lymphocytes during steady state conditions. Elsewhere in the body, ECs must be activated by exposure to inflammatory mediators in order to allow transendothelial migration to the inflamed tissue.
There is strong evidence to show the homing signature of a lymphocyte is dependent on the expression of adhesion molecules and chemokine receptors on the cell surface as well as their ligands expressed by the venular endothelium. Here, we hypothesize that the cytokine signaling receptor subunit glycoprotein 130 (gp130) is a functional requirement for eliciting an effective recruitment of lymphocytes to secondary lymphoid organs during steady states. Glycoprotein 130 is a signaling subunit involved with the interleukin-6 (IL-6) family of cytokines. Previous studies done in the lab have shown that this glycoprotein is over expressed in the venular versus non-venular endothelial cells, indicating a potential role of gp130 in lymphocyte homing during steady state conditions.
This hypothesis was tested by analyzing short term homing assays using donor β-actin-GFP splenocytes, with recipient litter-mate controls and recipient conditional or inducible conditional knockout mouse models that lack gp130 expression on ECs. By comparing the homing abilities of GFP+ splenocytes to various secondary lymphoid organs in wild type versus knockout mouse models, we were able to determine that gp130 expression on the endothelial cell compartment does have a role in lymphocyte homing, demonstrated by impaired homing capabilities evident in only the knockout mice.
Identifying the function of gp130 expressed by venular ECs and its role in lymphocyte recruitment during steady state conditions may lead to a better understanding of the immune system and it's complexity during the dynamic maintenance of homeostatic health.