Mrgprb2-dependent Mast Cell Activation Plays a Crucial Role in Acute Colitis.

BACKGROUND & AIMS: Mast cells (MCs) are typically found at mucosal surfaces, where their immunoglobulin E (IgE)-dependent activation plays a central role in allergic diseases. Over the past years, signaling through Mas-related G protein-coupled receptor b2 (Mrgprb2) in mice and MRGPRX2 in humans has gained a lot of interest as an alternative MC activation pathway with high therapeutic potential. The aim of this study was to explore the relevance of such IgE-independent, Mrgprb2-mediated signaling in colonic MCs in the healthy and acutely inflamed mouse colon. METHODS: Mrgprb2 expression and functionality was studied using a genetic labeling strategy combined with advanced microscopic imaging. Furthermore, Mrgprb2 knockout (Mrgprb2-/-) mice were used to determine the role of this pathway in a preclinical dextran sodium sulphate (DSS) colitis model. RESULTS: We found that Mrgprb2 acts as a novel MC degranulation pathway in a large subset of connective tissue MCs in the mouse distal colon. Acute DSS colitis induced a pronounced increase of Mrgprb2-expressing MCs, which were found in close association with Substance P-positive nerve fibers. Loss of Mrgprb2-mediated signaling impaired DSS-induced neutrophil influx and significantly impacted on acute colitis progression. CONCLUSIONS: Our findings uncover a novel, IgE-independent MC degranulation pathway in the mouse colon that plays a central role in acute colitis pathophysiology, mainly by safeguarding acute colitis progression and severity in mice. This pseudo allergic, Mrgprb2-induced signaling is part of a hitherto unconsidered colonic neuro-immune pathway and might have significant potential for the further development of effective therapeutic treatment strategies for gastrointestinal disorders, such as ulcerative colitis.

The orphan MRGPRF receptor is expressed in entero-endocrine cells of the human gut mucosa.

In the past years, it has become clear that the family of Mas-related G protein-coupled receptors plays a central role in neuro-immune communication at mucosal barrier surfaces, in particular in the skin. Remarkably, MRGPR expression at other mucosal surfaces remains poorly characterized. To fill this gap in our understanding, the present study was undertaken to screen and verify the expression of the human MRGPR family members in the mucosal biopsies of the human gastrointestinal (GI) tract. Our findings revealed that, of all human MRGPRs family members, only MRGPRF mRNA is expressed at detectable levels in human mucosal biopsies of both terminal ileum and sigmoid colon. Furthermore, immunohistochemical stainings revealed that MRGPRF is specifically expressed by mucosal entero-endocrine cells (EECs). Overall, this study showed for the first time that the human ileum and colonic mucosa represent a novel expression site for the orphan MRGPRF, more specifically in EECs.

Neuro-immune interactions and the role of Mas-related G protein-coupled receptors in the gastrointestinal tract.

Over the past decade, the research field dealing with the role of a new family of Rhodopsin A-like G protein-coupled receptors, that is, the family of Mas-related G protein-coupled receptors (Mrgprs) has expanded enormously. A plethora of recent studies have provided evidence that Mrgprs are key players in itch and pain, as well as in the initiation and modulation of inflammatory/allergic responses in the skin. Over the years, it has become clear that this role is not limited to the skin, but extends to other mucosal surfaces such as the respiratory tract and the gastrointestinal (GI) tract. In the GI tract, Mrgprs have emerged as novel interoceptive sensory pathways linked to health and disease, and are in close functional association with the gut's immune system. This review aims to provide an update of our current knowledge on the expression, distribution and function of members of this Mrgpr family in intrinsic and extrinsic neuro-immune pathways related to the GI system.