Research Report 2010 2011 - Helmholtz-Zentrum für ...

SCIENTIFIC REPORTS | Infection and Immunity | Infl ammation and Immunity 97
03.6 Inflammation and Regeneration
PROJECT LEADER | Priv.-Doz. Dr. Gerhard Gross | Department of Gene Regulation and Differentiation |
ggr@helmholtz-hzi.de
PROJECT MEMBERS | Dr. Thomas Böldicke | Markus Heine | Sandra Laggies | Dr. Virginia Seiffart |
Stefan Somplatzki | Lijing Sun | Dr. Herbert Weich | Dr. Manfred Wirth
Infection of tissues and trauma, shock and sepsis induce a
severe inflammatory response, the primary role of which is
to eliminate pathogens, promote tissue repair and return the
host to optimal normal function. In contrast to acute inflammation,
chronic inflammation leads to a progressive shift in
the type of cells which are present at the site of inflammation
and, in general, leads to the destruction of the tissue in or
near the inflammatory process often resisting regeneration.
We follow the hypothesis that inhibition of the inflammatory
signaling cascades will allow the design of new antiinflammatory
and therapeutic modalities. In this regard, we
investigate the role of caveolin-1 in inflammation in general
and in virus infection in particular. Caveolin-1 represents a
multifaceted membrane protein involved in cellular transport
and signaling. It interacts with the human influenza virus
matrix protein M2 and, moreover, modulates virus production.
Further investigation of M2/Caveolin-1 interaction and
its signal transduction pathways may, therefore, result in a
novel target for therapeutic intervention.
As another anti-inflammatory strategy we are developing
specific intrabodies which are able to retain the Toll-like
receptors 2 and 9 (TLR2 / TLR9) in the endoplasmic reticulum
(ER). We could already demonstrate that an adenovirus
vector-dependent, systemic expression of an anti-TLR2
intrabody has the capacity to provide resistance to a lethal
septic challenge with Bacillus subtilis. We will now focus
on the investigation whether or not TLR2- and the recently
constructed TLR9-intrabodies are able to interfere with a
chronic inflammatory disease such as rheumatoid arthritis.
Rheumatoid arthritis is a severe chronic, systemic, inflammatory,
autoimmune disorder that may affect many tissues
and organs but principally attacks and destroys synovial
joints. About 1% of the world‘s population is affected. This
disorder may lead to a substantial loss of mobility and, in
general, patients suffer from serious pain and are afflicted
by an increased mortality. Current therapies for rheumatoid
arthritis are often unsatisfactory and an ongoing search
for new therapeutic modalities is, therefore, required. We
recently showed that a novel systemic targeting strategy for a
central inflammatory signaling mediator (TGF-beta-activated
kinase-1; TAK1) using the RNAi technology dramatically alleviates
rheumatoid arthritis symptoms in a murine collageninduced
arthritis model. Down-regulation of TAK1 protects
the synovial joints from degradation and causes a significant
reduction of inflammatory Th1 and Th17 cells. TAK1 is,
there fore, a novel and attractive therapeutic target to interfere
with rheumatoid arthritis. At present, we aim to transfer
these results onto other chronic inflammatory disorders.
Angiogenesis and the activation of the blood vascular system
play important roles in sustaining a chronic inflammation. In
contrast, however, the role of the lymphatic vasculature in
chronic inflammation has remained unclear. We have established
novel potent isolation techniques which allowed for
the first time the isolation of human lymph endothelial cells
from normal skin and from diseased tissue (lymphangiomas).
In addition, we were successful in isolating mouse endothelial
progenitor cells from adult lungs which showed a bipotential
capacity to differentiate in vitro and in vivo into blood
endothelial cells and lymph endothelial cells. These primary
cells have been extensively compared and also subjected to
expression profiling to find genes as possible targets for the
therapy of inflammatory disorders.
In vitro differentiation of endothelial progenitor cells (EPCs)
from mouse lung: Bipotential capacity for the generation
of blood- and lymph-endothelial cells. Prox1, marker of
lymph-endothelial cells (green); marker of blood- and lymph
endothelial cell (red). Photo: HZI
Becker, J., Pavlakovic, H., Ludewig, F., Wilting, F., Weich, H.A., Albuquerque, R., Ambati,
J., & Wilting,J. (2010) Neuroblastoma progression correlates with downregulation of the
lymphangiogenesis inhibitor sVEGFR-2. Clinical Cancer Research 16, 1431-1441.
Charbord, P., Livne, E., Gross, G., Haupl, T., Neves, N. M., Marie, P., Bianco, P., & Jorgensen,
C. (2010) Human bone marrow mesenchymal stem cells: A systematic reappraisal
via the genostem experience. Stem Cell Review, in press
Courties, G., Seiffart, V., Presumey, J., Escriou, V., Scherman, D., Zwerina, J., Riuz, G.,
Zietara, N., Jablonska-Koch, J., Weiss, S., Hoffmann, A., Jorgensen, C., Apparailly, F., &
Gross, G. (2010) In vivo RNAi-mediated silencing of TAK1 decreases inflammatory Th1
and Th17 cells through targeting of myeloid cells. Blood, in press.