Exploring the function of vascular IL-33 in the rat

Interleukin-33 is a recently identified member of the IL-1 cytokine family and currently an attractive drug target in asthma, yet the bulk of experimental in vivo data comes from interventional experiments in the laboratory mouse. Nevertheless, our mapping of IL-33 expression in several species has demonstrated that the mouse is very different from man, and murine disease models are therefore questionable when it comes to understanding all functions of this cytokine. In particular, while expression of IL-33 in vascular endothelial cells is almost absent in the mouse, it is prominent in man and in rats.

Endothelial cells form the innermost layer of vessel walls, and their activation is important for the recruitment of white blood cells to inflammatory lesions and for the formation of new blood vessels. We wish to know how IL-33 in vascular endothelial cells affects inflammation and we have therefore generated IL-33-deficient Sprague-Dawley rats

We propose to conduct multiple experiments, with special focus on:

1
The role of IL-33 in formation, maturation and barrier function of blood vessels (Matrigel plug assay, Luconyl blue)

2
The role of IL-33 in targeted leukocyte recruitment to tissues (LPS in skin)

3
The role of IL-33 in systemic inflammatory response syndrome (LPS i.v.)

4
The role of IL-33 in ischemia reperfusion injury (renal clamping)

The experiments proposed here will significantly expand current knowledge and facilitate translation to human physiology and pathology.