Prostaglandine D2 et homéostasie de la barrière épithéliale intestinale

La prostaglandine D2 (PGD2) et ses dérivés sont des médiateurs lipidiques participant à l’homéostasie de la barrière épithéliale intestinale. Leur implication dans la physiopathologie des maladies inflammatoires chroniques de l’intestin reste encore débattue. Plusieurs résultats soulignent la dualité de la PGD2 quant à son rôle anti- ou pro-inflammatoire. Cette dualité semble liée à une expression différentielle de ses récepteurs par les cellules épithéliales intestinales et par les cellules immunocompétentes environnantes. Les cellules gliales du système nerveux entérique sont capables de sécréter ces médiateurs. Le rôle protecteur du système nerveux entérique dans le contrôle de l’homéostasie de la barrière épithéliale intestinale a été démontré. Ainsi, la PGD2 et ses dérivés se révèlent être de nouveaux acteurs de l’unité neuro-glio-épithéliale impliqués dans la régulation des fonctions des cellules épithéliales intestinales

Activation of the prostaglandin D2 metabolic pathway in Crohn’s disease: involvement of the enteric nervous system

Background: Recent works provide evidence of the importance of the prostaglandin D2 (PGD2) metabolic pathway in inflammatory bowel diseases. We investigated the expression of PGD2 metabolic pathway actors in Crohn's disease (CD) and the ability of the enteric nervous system (ENS) to produce PGD2 in inflammatory conditions.Methods: Expression of key actors involved in the PGD2 metabolic pathway and its receptors was analyzed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in colonic mucosal biopsies of patients from three groups: controls, quiescent and active CD patients. To determine the ability of the ENS to secrete PGD2 in proinflammatory conditions, Lipocalin-type prostaglandin D synthase (L-PGDS) expression by neurons and glial cells was analyzed by immunostaining. PGD2 levels were determined in a medium of primary culture of ENS and neuro-glial coculture model treated by lipopolysaccharide (LPS).Results: In patients with active CD, inflamed colonic mucosa showed significantly higher COX2 and L-PGDS mRNA expression, and significantly higher PGD2 levels than healthy colonic mucosa. On the contrary, peroxysome proliferator-activated receptor Gamma (PPARG) expression was reduced in inflamed colonic mucosa of CD patients with active disease. Immunostaining showed that L-PGDS was expressed in the neurons of human myenteric and submucosal plexi. A rat ENS primary culture model confirmed this expression. PGD2 levels were significantly increased on primary culture of ENS treated with LPS. This production was abolished by AT-56, a specific competitive L-PGDS inhibitor. The neuro-glial coculture model revealed that each component of the ENS, ECG and neurons, could contribute to PGD2 production.Conclusions: Our results highlight the activation of the PGD2 metabolic pathway in Crohn's disease. This study supports the hypothesis that in Crohn's disease, enteric neurons and glial cells form a functional unit reacting to inflammation by producing PGD2