GDNF protects enteric glia from apoptosis: evidence for an autocrine loop

Abstract

BackgroundEnteric glia cells (EGC) play an important role in the maintenance of intestinal mucosa integrity. During the course of acute Crohn's disease (CD), mucosal EGC progressively undergo apoptosis, though the mechanisms are largely unknown. We investigated the role of Glial-derived neurotrophic factor (GDNF) in the regulation of EGC apoptosis.MethodsGDNF expression and EGC apoptosis were determined by immunofluorescence using specimen from CD patients. In primary rat EGC cultures, GDNF receptors were assessed by western blot and indirect immunofluorescence microscopy. Apoptosis in cultured EGC was induced by TNF-α and IFN-γ, and the influence of GDNF on apoptosis was measured upon addition of GDNF or neutralizing anti-GDNF antibody.ResultsIncreased GDNF expression and Caspase 3/7 activities were detected in in specimen of CD patients but not in healthy controls. Moreover, inactivation of GDNF sensitized in EGC cell to IFN-γ/TNF-α induced apoptosis.ConclusionsThis study proposes the existence of an autocrine anti-apoptotic loop in EGC cells which is operative in Crohn's disease and dependent of GDNF. Alterations in this novel EGC self-protecting mechanism could lead to a higher susceptibility towards apoptosis and thus contribute to disruption of the mucosal integrity and severity of inflammation in CD.

Neurotrophic factors in enteric physiology and pathophysiology

“…Similarly, gastric electrical stimulation prevented vagotomy‐induced apoptosis of enteric neurons in the stomach, which was mediated by enhanced release of GDNF and activation of its downstream pathway PI3K/Akt . GDNF was also found to protect enteric glial cells from apoptosis induced by gut inflammation through an autocrine mechanism in enteric glial cells …”

“…44 GDNF was also found to protect enteric glial cells from apoptosis induced by gut inflammation through an autocrine mechanism in enteric glial cells. 45 Although BDNF has been known to have neuroprotective effects in the central nervous system, the evidence for neuroprotection in the ENS is scarce. BDNF was shown to inhibit inflammation-induced apoptosis in enteric glial cells.…”

Enteric Glial Cells: Recent Developments and Future Directions

“…These mediators can increase neuronal as well as epithelial survival. 20,[53][54][55] Altogether, these studies suggest that a similar shift in paradigm could occur for EGCs as for astrocytes in the brain. Indeed, reactive astrocytes of the CNS have long been considered to be deleterious before being increasingly recognized as essential actors of tissue repair after injury.…”

The Enteric Glia: Identity and Functions

“…Enteric glial cells also function in gut inflammatory processes by increasing the expression of neurotrophic factors such as GDNF, BDNF, and NGF. In IBD, GDNF has an antiapoptotic effect on intestinal epithelial cells and also on enteric glial cells, functioning as a protective feedback loop (Steinkamp et al, ). Another neurotrophic factor with antiapoptotic effects for the enteric glia is BDNF (Steinkamp et al, ).…”