TY  - JOUR
A1  - Meir, Michael
A1  - Kannapin, Felix
A1  - Diefenbacher, Markus
A1  - Ghoreishi, Yalda
A1  - Kollmann, Catherine
A1  - Flemming, Sven
A1  - Germer, Christoph-Thomas
A1  - Waschke, Jens
A1  - Leven, Patrick
A1  - Schneider, Reiner
A1  - Wehner, Sven
A1  - Burkard, Natalie
A1  - Schlegel, Nicolas
T1  - Intestinal epithelial barrier maturation by enteric glial cells is GDNF-dependent
JF  - International Journal of Molecular Sciences
N2  - Enteric glial cells (EGCs) of the enteric nervous system are critically involved in the maintenance of intestinal epithelial barrier function (IEB). The underlying mechanisms remain undefined. Glial cell line-derived neurotrophic factor (GDNF) contributes to IEB maturation and may therefore be the predominant mediator of this process by EGCs. Using GFAP\(^{cre}\) x Ai14\(^{floxed}\) mice to isolate EGCs by Fluorescence-activated cell sorting (FACS), we confirmed that they synthesize GDNF in vivo as well as in primary cultures demonstrating that EGCs are a rich source of GDNF in vivo and in vitro. Co-culture of EGCs with Caco2 cells resulted in IEB maturation which was abrogated when GDNF was either depleted from EGC supernatants, or knocked down in EGCs or when the GDNF receptor RET was blocked. Further, TNFα-induced loss of IEB function in Caco2 cells and in organoids was attenuated by EGC supernatants or by recombinant GDNF. These barrier-protective effects were blunted when using supernatants from GDNF-deficient EGCs or by RET receptor blockade. Together, our data show that EGCs produce GDNF to maintain IEB function in vitro through the RET receptor.
KW  - enteric glial cells
KW  - neurotrophic factors
KW  - intestinal epithelial barrier
KW  - GDNF5
KW  - RET6
KW  - inflammatory bowel disease
KW  - enteric nervous system
KW  - gut barrier
KW  - intercellular junctions
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258913
SN  - 1422-0067
VL  - 22
IS  - 4
ER  - 
TY  - JOUR
A1  - Rosenbaum, Corinna
A1  - Schick, Martin Alexander
A1  - Wollborn, Jakob
A1  - Heider, Andreas
A1  - Scholz, Claus-Jürgen
A1  - Cecil, Alexander
A1  - Niesler, Beate
A1  - Hirrlinger, Johannes
A1  - Walles, Heike
A1  - Metzger, Marco
T1  - Activation of Myenteric Glia during Acute Inflammation In Vitro and In Vivo
JF  - PLoS One
N2  - Background
Enteric glial cells (EGCs) are the main constituent of the enteric nervous system and share similarities with astrocytes from the central nervous system including their reactivity to an inflammatory microenvironment. Previous studies on EGC pathophysiology have specifically focused on mucosal glia activation and its contribution to mucosal inflammatory processes observed in the gut of inflammatory bowel disease (IBD) patients. In contrast knowledge is scarce on intestinal inflammation not locally restricted to the mucosa but systemically affecting the intestine and its effect on the overall EGC network.

Methods and Results
In this study, we analyzed the biological effects of a systemic LPS-induced hyperinflammatory insult on overall EGCs in a rat model in vivo, mimicking the clinical situation of systemic inflammation response syndrome (SIRS). Tissues from small and large intestine were removed 4 hours after systemic LPS-injection and analyzed on transcript and protein level. Laser capture microdissection was performed to study plexus-specific gene expression alterations. Upon systemic LPS-injection in vivo we observed a rapid and dramatic activation of Glial Fibrillary Acidic Protein (GFAP)-expressing glia on mRNA level, locally restricted to the myenteric plexus. To study the specific role of the GFAP subpopulation, we established flow cytometry-purified primary glial cell cultures from GFAP promotor-driven EGFP reporter mice. After LPS stimulation, we analyzed cytokine secretion and global gene expression profiles, which were finally implemented in a bioinformatic comparative transcriptome analysis. Enriched GFAP+ glial cells cultured as gliospheres secreted increased levels of prominent inflammatory cytokines upon LPS stimulation. Additionally, a shift in myenteric glial gene expression profile was induced that predominantly affected genes associated with immune response.

Conclusion and Significance
Our findings identify the myenteric GFAP-expressing glial subpopulation as particularly susceptible and responsive to acute systemic inflammation of the gut wall and complement knowledge on glial involvement in mucosal inflammation of the intestine.
KW  - gene expression
KW  - gastrointestinal tract
KW  - inflammatory bowel disease
KW  - central nervous system
KW  - systemic inflammatory response syndrome
KW  - inflammation
KW  - astrocytes
KW  - cytokines
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146544
VL  - 11
IS  - 3
ER  -