The arachidonic acid metabolite 11β-ProstaglandinF2α controls intestinal epithelial healing: deficiency in patients with Crohn's disease.

Compelling evidence has demonstrated that defects in mucosal healing are central to Crohn’s Disease (CD) pathogenesis and prognosis. In particular several studies have reported that intestinal mucosal lesions precede inflammation and are considered as a predictive factor of relapse1,2,3. Mucosal healing has further been suggested to represent a treatment goal and a predictive factor for sustained clinical remission in CD4,5,6. The intestinal epithelium is a dynamic interface between the environment and the organism that must constantly preserve its integrity to maintain digestive and barrier functions. After injury, mucosal repair is a key process to restore epithelium lining and functions such as permeability control leading ultimately to intestinal homeostasis. Three main concomitant regenerative processes participate to mucosal healing and include epithelial restitution, that involves cell spreading and migration into the wound, cell proliferation and differentiation7. It has now been well demonstrated that IEB functions, including intestinal healing, are regulated by neighboring cells, the so-called microenvironment, and in particular the enteric nervous system (ENS)8. The ENS is an integrative neuronal network localized along the gastrointestinal tract that regulates key digestive functions such as gut motility and mucosal secretion9,10. ENS is composed of enteric neurons and enteric glial cells (EGC) that outnumber enteric neurons by a factor of 4 to 1011 and share common markers and functional properties with central nervous system astrocytes12,13,14,15,16. EGC form a dense network that surrounds intestinal crypts, and are located at less than 2 μm from intestinal epithelial cells (IECs). A large number of studies from our group and others have now well demonstrated that EGC are key regulators of IEB homeostasis and functions17,18. In particular EGC impact IEC major functions via paracrine signaling. For instance they inhibit IEC proliferation via the release of transforming growth factor-β (TGF-β) and 15-deoxy-delta12,14-Prostaglandin J2 (15dPGJ2), a derivative of n-6 (omega-6) polyunsaturated fatty acids (PUFA), and activation of Peroxisome proliferator-activated receptorγ (PPARγ)-dependent pathways19,20. Importantly, EGC promote mucosal healing via enhanced cell spreading/restitution and pro-epidermal growth factor (proEGF) secretion21 and decrease intestinal permeability via S-nitrosoglutathione (GSNO) production22. Of major interest, EGC ablation in transgenic murine models leads to histopathological alterations reminiscent to CD23,24,25. Some human studies have reported abnormalities of the EGC network in CD patients with mostly altered expression of EGC markers such as S100β and GFAP25,26,27. However whether CD EGC have altered ability to regulate IEC functions remains largelly unknown. A very recent study has shown that EGC of CD patients have reduced ability to regulate paracellular permeability28 but their impact on the control of IEB repair remains currently unknonwn. In this study, we hypothesized that CD EGC will show impaired functional phenotype as compared to ‘healthy’ EGC, thus participating to CD-associated defects in IEB mucosal healing. Using a non-contact co-culture model of human EGC isolated from CD or control patients and IEC, we assessed whether CD EGC have differential impact on IEC sealing, spreading and healing than control EGC, and we identified glial-soluble factors and signaling pathways involved.