Research interests

Vascular endothelial cells are central players in the initiation and amplification of inflammatory responses, and their role in recruiting leukocytes to inflammatory lesions by expressing adhesion molecules and chemokines is now well characterized. On the other hand, we are only beginning to understand the mechanisms that control their level of quiescence and general responsiveness to proinflammatory mediators. Moreover, mechanisms that regulate the generation of new vessels and endothelial cell differentiation/activation are potential drug targets that may enable control of cancer growth and metastasis, enhance the healing of ischemic lesions and modulate the leukocyte migration of inflammatory disorders including transplant rejection.

Our studies have added to this picture: in 2003 we cloned a nuclear factor of high endothelial venules (NF-HEV) that later turned out to be a novel member of the interleukin-1 family of cytokines and be renamed interleukin-33 (IL-33). We showed that IL-33 is a marker of endothelial cells quiescence (Küchler et al, Am J Pathol, 2008) and discovered that Notch-signalling driven by Dll4 is sufficient and necessary to induce and maintain IL-33 expression in vascular endothelial cells (Sundlisæter et al, Am J Pathol, 2012). We also proposed that it would act as an alarmin once released from damaged cells (Haraldsen et al, Trends Immunol 2009) and demonstrated that IL-33 is a predominant mediator of wound healing expressed by myofibroblasts (Sponheim et al, Am J Pathol, 2010). Recently, we were able to demonstrate that when IL-33 is released to the extracellular environment it selectively activates non-quiescent endothelial cells (Pollheimer et al, ATVB, 2012)

In a second line of experiments, based on establishing the first transcriptional profile of endothelial cells during experimental allograft rejection (Mikalsen et al, Am J Transplant, 2010) we are pursuing the characterisation of matricellular proteins periostin and tenascin C in clinical kidney allografts. In this context we are mapping the effect of IL-33 in regulation of these proteins (Hammarstrøm et al, in preparation) and have established a model of kidney fibrosis based on ureter obstruction (UUO model) to study the development of fibrosis in IL-33-deficient mice.

In a third line of experiments we are unravelling the role of Notch signalling in endothelial cell activation, having demonstrated that the Notch ligand Jagged-1 promotes the expression of proinflammatory adhesion molecules and chemokines

In a fourth line of studies we have in a collaboration with Alexandre Corthay and colleagues contributed to a study that shows how proinflammatory cytokines contribute to host tumor defence in a model of B-cell cancer (Haabeth et al, Nature Communications 2011; 2:240). This continues, based on observing that Th2 cells also have the ability to reject tumors and we are now dissecting the cellular mediators of this process to understand the mechanisms of this kind of tumor immunity.

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