Search

Increasing evidence suggests that enteric glial cells (EGCs) are critical for enteric neuron survival and functions. In particular, EGCs exert direct neuroprotective effects mediated in part by the release of glutathione. However, other glial factors such as those identified as regulating the intestinal epithelial barrier and in particular the omega-6 fatty acid derivative 15-deoxy-Δ¹²,¹⁴-prostaglandin J2 (15d-PGJ2) could also be involved in EGC-mediated neuroprotection. Therefore, our study aimed to assess the putative role of EGC-derived 15d-PGJ2 in their neuroprotective effects. We first showed that pretreatment of primary cultures of enteric nervous system(ENS)or humann euroblastoma cells (SH-SY5Y)with 15d-PGJ2 dose dependently prevented hydrogen peroxide neurotoxicity. Furthermore, neuroprotective effects of EGCs were significantly inhibited following genetic invalidation in EGCs of the key enzyme involved in 15d-PGJ2 synthesis, i.e. L-PGDS. We next showed that 15d-PGJ2 effects were mediated by an Nrf2 dependent pathway but were not blocked by PPARγ inhibitor (GW9662) in SH-SY5Y cells and enteric neurons. Finally, 15d-PGJ2 induced a significant increase in glutamate cysteine ligase expression and intracellular glutathione in SH cells and enteric neurons. In conclusion, we identified 15d-PGJ2 as a novel glial-derived molecule with neuroprotective effects in the ENS. This study further supports the concept that omega-6 derivatives such as 15d-PGJ2 might be used in preventive and/or therapeutic strategies for the treatment of enteric neuropathies.

The enteric nervous system (ENS) and its major component, enteric glial cells (EGCs), have recently been identified as a major regulator of intestinal epithelial barrier functions. Indeed, EGCs inhibit intestinal epithelial cell (IEC) proliferation and increase barrier resistance and IEC adhesion via the release of EGC-derived soluble factors. Interestingly, EGC regulation of intestinal epithelial barrier functions is reminiscent of previously reported peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent functional effects. In this context, the present study aimed at identifying whether EGC could synthesize and release the main PPARgamma ligand, 15-deoxy-(12,14)-prostaglandin J2 (15dPGJ2), and regulate IEC functions such as proliferation and differentiation via a PPARgamma dependent pathway. First, we demonstrated that the lipocalin but not the haematopoetic form for prostaglandin D synthase (PGDS), the enzyme responsible of 15dPGJ2 synthesis, was expressed in EGCs of the human submucosal plexus and of the subepithelium, as well as in rat primary culture of ENS and EGC lines. Next, 15dPGJ2 was identified in EGC supernatants of various EGC lines. 15dPGJ2 reproduced EGC inhibitory effects upon IEC proliferation, and inhibition of lipocalin PGDS expression by shRNA abrogated these effects. Furthermore, EGCs induced nuclear translocation of PPARgamma in IEC, and both EGC and 15dPGJ2 effects upon IEC proliferation were prevented by the PPARgamma antagonist GW9662. Finally, EGC induced differentiation-related gene expression in IEC through a PPARgamma-dependent pathway. Our results identified 15dPGJ2 as a novel glial-derived mediator involved in the control of IEC proliferation/differentiation through activation of PPARgamma. They also suggest that alterations of glial PGDS expression may modify intestinal epithelial barrier functions and be involved in the development of pathologies such as cancer or inflammatory bowel diseases.