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Inflammation and Vascular Biology

The response of tissue-resident cells to infection or trauma incites an inflammatory response that leads to activation of vascular endothelial cells. Once activated, they are key 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 how proinflammatory responsiveness can be modulated.

Schematic representation of IL-33 induction in fibroblasts, pericytes, and myofibroblasts during wound healing. Stromal, tissue-resident, fibroblasts (IL-33 positive or negative) are activated by mRNA/TGF/lipopolysaccharide to express nuclear IL-33 (red nuclei) and may contribute to the pool of myofibroblasts invading the wound area. Likewise, pericytes become activated and may contribute to this pool. By contrast, vascular endothelial cells, which are strongly positive in healthy tissue, down-regulate IL-33 in the course of activation.

Mechanisms that regulate endothelial cell differentiation/activation are potential drug targets that may enable enhance the healing of ischemic lesions, modulate the leukocyte migration of inflammatory disorders including transplant rejection, and control of cancer growth and metastasis. Morover, other stromal cell types are also strongly involved in the development of the inflammatory response. Persistent inflammatory activation leads to tissue damage and development of fibrosis and subsequent fibrosis with loss of organ function.


Studies from our group 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 was renamed interleukin-33 (Bækkevold et al, Am J Pathol 2003). We showed that this nuclear cytokine was predominantly expressed in non-dividing, quiescent endothelial cells (Küchler et al, Am J Pathol, 2008) and proposed that IL-33 might act as an alarmin once released from damaged or necrotic cells (Haraldsen et al, Trends Immunol 2009). We also demonstrated that when IL-33 is released to the extracellular environment it selectively activates non-quiescent endothelial cells (Pollheimer et al, ATVB, 2012). While ongoing studies are designed to find IL-33-binding proteins in human endothelial cells, murine endothelial cells express very low levels of IL-33 and make transgenic mice unsuitable to study the vascular function of IL-33. We are therefore generating IL-33-deficient rats to circumvent this shortcoming.
  • 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. We demonstrated that IL-33 is a predominant mediator of wound healing expressed by myofibroblasts (Sponheim et al, Am J Pathol, 2010) and observed a strong induction of nuclear IL-33 in fibroblasts of the UUO response. Ongoing studies are characterizing a role for nuclear IL-33 in modulating the TGFß response of fibroblasts.
  • In a third line of experiments, based on our discovery 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 discovered that another Notch ligand (Jagged-1) promotes the expression of proinflammatory adhesion molecules and chemokines. An ongoing study has revealed the potential to exploit inhibition of Notch signalling as a novel principle of anti-inflammatory therapy.
  • In a fourth line of experiments, we have characterized the regulation of IL-33 in dermal keratinocytes and revealed important species-differences (Utnes et al, J Invest Dermatol 2015) that call for vigilant interpretation of experimental assessment of IL-33 function in inflammatory skin disease. Ongoing studies are focussed on characterising an entirely novel, stress-induced mechanism of IL-33 in skin disease.
Published Dec. 4, 2012 10:25 PM - Last modified May 14, 2020 12:50 PM