Abstract
Enteric glial cells (EGC) actively mediate acute and chronic inflammation in the gut; EGC proliferate and release neurotrophins, growth factors, and pro-inflammatory cytokines which, in turn, may amplify the immune response, representing a very important link between the nervous and immune systems in the intestine. Cannabidiol (CBD) is an interesting compound because of its ability to control reactive gliosis in the CNS, without any unwanted psychotropic effects. Therefore the rationale of our study was to investigate the effect of CBD on intestinal biopsies from patients with ulcerative colitis (UC) and from intestinal segments of mice with LPS-induced intestinal inflammation. CBD markedly counteracted reactive enteric gliosis in LPS-mice trough the massive reduction of astroglial signalling neurotrophin S100B. Histological, biochemical and immunohistochemical data demonstrated that S100B decrease was associated with a considerable decrease in mast cell and macrophages in the intestine of LPS-treated mice after CBD treatment. Moreover the treatment of LPS-mice with CBD reduced TNF-α expression and the presence of cleaved caspase-3. Similar results were obtained in ex vivo cultured human derived colonic biopsies. In biopsies of UC patients, both during active inflammation and in remission stimulated with LPS+INF-γ, an increased glial cell activation and intestinal damage were evidenced. CBD reduced the expression of S100B and iNOS proteins in the human biopsies confirming its well documented effect in septic mice. The activity of CBD is, at least partly, mediated via the selective PPAR-gamma receptor pathway. CBD targets enteric reactive gliosis, counteracts the inflammatory environment induced by LPS in mice and in human colonic cultures derived from UC patients. These actions lead to a reduction of intestinal damage mediated by PPARgamma receptor pathway. Our results therefore indicate that CBD indeed unravels a new therapeutic strategy to treat inflammatory bowel diseases.
Highlights
Despite the ancient assumption that enteric glial cells (EGC) may serve as a mere mechanical support for enteric neurons, nowadays the knowledge on these cells is consistently expanded
In the present study we investigated the effect of CBD, as a possible modulator of the gut neuro-immune axis, based on its ability to control both inflammatory response, during intestinal inflammation, and EGC activation
We found that the LPS-induced inflammatory response in mice intestine resulted in an increased expression of S100B, a protein that is exclusively localized in glial cells [19,20]
Summary
Despite the ancient assumption that enteric glial cells (EGC) may serve as a mere mechanical support for enteric neurons, nowadays the knowledge on these cells is consistently expanded. EGC play important functions in the maintenance of the enteric nervous system (ENS) homeostasis, but they may proliferate and be activated in response to injury and inflammation undergoing reactive gliosis (entero-gliosis), a dynamic process [4]. Abnormalities in the enteroglial network were described in the intestinal mucosa of patients with inflammatory bowel diseases (IBD) [8], measures as the reactive enteric gliosis, i.e. the massive over-expression and secretion of S100B protein, a cell-specific astroglial derived signalling molecule [9]. S100B protein, which is released by enteric glial cells, emerges as a pivotal signal molecule that extensively participates in the onset and in the progression of the inflammatory status as it orchestrates a wide range of signal activation pathways, directly correlated with the severity of gut degenerative processes [8]
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