Mas-related G protein-coupled receptors as novel mediators of gastro-intestinal neuro-immune communication

About two decades ago, a novel family of G protein-coupled receptors (GPCRs), termed Mas-related G protein-coupled receptors (Mrgprs), was discovered. Mrgprs are known for their role in the skin neuronal innervation, where they play a central role in the sensation of harmful or painful stimuli, such as pain and itch. The gastrointestinal (GI) tract, just like the skin, is a mucosal surface that is densely innervated by intrinsic and extrinsic neuronal circuitries that control GI functioning. Interestingly, although GI neuronal circuitries operate via distinct neuro-anatomical pathways, they share many receptors, ion channels and signaling pathways with the skin neuronal circuitries. Given these clear parallels, a role for Mrgprs in the GI tract seems plausible, but is currently still poorly characterized. Therefore, the present doctoral work aimed at providing a more profound understanding of the expression and role of Mrgprs in the GI tract and its innervation. This doctoral work showed that the neuronal pathways responsible for GI pain signaling (i.e. extrinsic spinal afferent dorsal root ganglia (DRG)) are a novel expression site for two Mrgpr family members, mouse Mrgprd and Mrgprc11. Furthermore, in vivo functional studies revealed that mouse Mrgprc11 is a driver of visceral hypersensitivity and abnormally increased pain sensitivity from the GI tract, and the translational potential of these findings to humans was demonstrated. Finally, we explored the expression of Mrgprs in the mucosa of the human GI tract and found that human MRGPRF is specifically expressed in a population of enteroendocrine cells. In addition, in a pilot study in IBS patients, we provided a first indication that MRGPRF might play a role in the IBS-affected mucosa, since its expression tended to be downregulated at the mRNA level in mucosal biopsies of IBS-D patients. Overall, the results obtained in this doctoral work confirm that the GI tract and its innervation is a novel site for Mrgpr expression. More importantly, our findings put Mrgprs on the map as possible novel therapeutic targets in GI pain research and neuro-immune communication, and suggest that further research is warranted on their role in the pathophysiology of debilitating GI disorders such as Inflammatory Bowel Diseases (IBD) and Irritable Bowel Syndrome (IBS).

Publication year:2020

Keywords:Doctoral thesis

Accessibility:Open