Presence of MrgprD within the gastrointestinal wall: reality or fake?

Due to their pivotal role in nociception and mast cell biology, the family of Mas-related G protein-coupled receptors (Mrgprs) has recently gained attention for their possible expression and role(s) in the gastrointestinal tract. In this context, based on immunocytochemical stainings using a commercial antibody, a recent study by Zhou et al. reported that the murine Mrgprd member is expressed in mouse gut lamina propria immune cells and in the outer smooth muscle layers pointing to a potential role for MrgprD in inflammatory responses and intestinal immunity. Immunohistochemical staining for G protein-coupled receptors (GPCRs), however, remains challenging and should be cautiously interpreted using appropriate specificity controls. Using the same antibody with an identical dilution, we did observe a similar staining in the same wild-type mouse strain, but an identical staining pattern was also found in mice lacking the MrgprD receptor, indicating that this antibody recognizes epitopes other than those of MrgprD. Moreover, in situ hybridization for MrgprD further indicated the absence of receptor mRNA expression in lamina propria immune cells and in the outer smooth muscle layers. Therefore, the results and conclusions regarding the presence of MrgprD at protein level within the GI wall as described in the study of Zhou and collaborators should be interpreted with strong caution and should be reconsidered in the light of the emerging possible roles of MrgprD and therapeutic perspectives in gastrointestinal pathophysiology.