Forum for Nordic Dermato-Venereology Nr2,2017 | Page 17
Dissertation
Interleukin-33 at Epidermal and Endothelial Barriers in Humans
O lav S undnes
Oslo University Hospital, Oslo, Norway. E-mail: [email protected]
Olav Sundnes, who is a dermatology resident at the Oslo University Hospital, defended his thesis on March 31,
2017, titled «Interleukin-33 at human epidermal and endothial barriers» for the degree of PhD at the University
of Oslo. Main supervisors were Guttorm Haraldsen and Denis Khnykin.
‘Alarmins’ are endogenous molecules that are constitutively
available and, when released upon cell death or damage, acti-
vates the immune system. These alarm signals are thus likely
the most proximal mediators of inflammatory responses after
tissue damage. Interleukin-33 (IL-33) is a novel IL-1 family
member and putative alarmin thought to have broad effects
on the immune system. However, most of our knowledge of
this molecule is based on animal models. The aim of this thesis
was therefore to investigate the biology of human IL-33 with
a special focus on the human epidermis and endothelium.
In the first part of the thesis, using carefully validated immuno-
histochemistry, we defined the expression of IL-33 in human
skin where endothelial cells were the main IL-33 reservoirs in
healthy homeostasis (1). Keratinocytes did not show constitu-
tive expression, but instead strongly upregulated IL-33 during
the inflammatory setting of experimentally induced wound
healing. This pattern of expression was markedly different
from murine skin, thus identifying potentially important
species differences.
We also characterized distinct modes of regulation of IL-33 in
human keratinocytes, confirmed in skin organ cultures, includ-
ing a novel mechanism of IL-33 induction by hypoosmotic
stress (2). Importantly, IL-33 showed nuclear localization in
all settings, with no evidence of active release.
To investigate the behaviour of IL-33 as an alarmin in vivo, we
analysed serially collected blood samples from trauma patients,
and were for the first time able to confirm systemic release of
human IL-33 after tissue damage (3). Finally, we studied the
effect of extracellular IL-33 on endothelial cells, finding that
Forum for Nord Derm Ven 2017, Vol. 22, No. 2
only nonquiescent cell responds due to a novel regulation
mechanism of the IL-33 receptor (4).
The studies provide new insight into the biology of human
IL-33 and will hopefully contribute to a better understanding
of the role of IL-33 in human disease.
List of original publications
1. Sundnes O, Pietka W, Loos T, Sponheim J, Rankin AL, Pflanz S, et
al. Epidermal Expression and Regulation of Interleukin-33 during
Homeostasis and Inflammation: Strong Species Differences. J Invest
Dermatol 2015; 135: 1–10.
2. Sundnes O, Pietka W, Bertelsen V, Stav-Noraas T-E, Galtung HK,
Khnukin D, et al. Hypoosmotic stress drives IL-33 production in hu-
man keratinocytes – a novel epidermal stress response. Manuscript.
3. Sundnes O, Ottestad W, Schjalm C, la Cour Poulsen L, Mollnes
TE, Haraldsen G, et al. IL-33 is rapidly released to the systemic
circulation during severe trauma in humans. Manuscript.
4. Pollheimer J, Bodin J, Sundnes O, Edelmann RJ, Skånland SS, Spon-
heim J, et al. Interleukin-33 drives a proinflammatory endothelial
activation that selectively targets nonquiescent cells. Arterioscler
Thromb Vasc Biol 2013; 33: e47–55.
47