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  - 
TY  - JOUR
A1  - Wohlfarth, Carolin
A1  - Schmitteckert, Stefanie
A1  - Härtle, Janina D.
A1  - Houghton, Lesley A.
A1  - Dweep, Harsh
A1  - Fortea, Marina
A1  - Assadi, Ghazaleh
A1  - Braun, Alexander
A1  - Mederer, Tanja
A1  - Pöhner, Sarina
A1  - Becker, Philip P.
A1  - Fischer, Christine
A1  - Granzow, Martin
A1  - Mönnikes, Hubert
A1  - Mayer, Emeran A.
A1  - Sayuk, Gregory
A1  - Boeckxstaens, Guy
A1  - Wouters, Mira M.
A1  - Simrén, Magnus
A1  - Lindberg, Greger
A1  - Ohlsson, Bodil
A1  - Schmidt, Peter Thelin
A1  - Dlugosz, Aldona
A1  - Agreus, Lars
A1  - Andreasson, Anna
A1  - D'Amato, Mauro
A1  - Burwinkel, Barbara
A1  - Bermejo, Justo Lorenzo
A1  - Röth, Ralph
A1  - Lasitschka, Felix
A1  - Vicario, Maria
A1  - Metzger, Marco
A1  - Santos, Javier
A1  - Rappold, Gudrun A.
A1  - Martinez, Cristina
A1  - Niesler, Beate
T1  - miR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome
JF  - Scientific Reports
N2  - Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT4R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.*61 T > C within the 5-HT4 receptor gene \(HTR4\) to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms \({HTR4b/i}\) and putatively impairs \(HTR4\) expression. Subsequent miRNA profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. \(In\) \(vitro\) assays confirmed expression regulation via three 3′UTR binding sites. The novel isoform \(HTR4b\_2\) lacking two of the three miRNA binding sites escapes miR-16/103/107 regulationin SNP carriers. We provide the first evidence that \(HTR4\) expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.*61 T > C or bydiminished levels of miR-16 and miR-103 suggesting that \(HTR4\) might be involved in the development of IBS-D.
KW  - Medicine
KW  - Gene regulation
KW  - Irritable bowel syndrome
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173478
VL  - 7
ER  -