Mas-related G protein coupled receptor X2 (MRGPRX2), a paradigm change in mast cell biology, elicits non-allergic activation: insights into functional programs, signaling cascades, desensitization and cross-regulation between the allergic and the pseudo-allergic pathway in human skin mast cells

• Applicant: Dr. Magda Babina
• Subject Area: Dermatology ; Immunology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 423161438

As hypothesized in the first application, MRGPRX2 has evolved into a highly active field, and is now widely accepted as the “missing link” in pathology related to mast cell (MC) activation without the necessity of adaptive immunity. As a potent inducer of degranulation, MRGPRX2 shares properties with the canonical FceRI/IgE/allergen pathway. As we have learned during a first fruitful funding period, it varies in many other respects, however. Differences apply to signal transduction (MRGPRX2 rapid/FceRI delayed), cytokine production (MRGPRX2 less potent), and regulation by cues from the skin micromilieu. Interestingly, the two systems can also engage in a close dialogue acting either as opponents (in a timely shifted manner) or as cooperators (when stimulated simultaneously). When danger is communicated to MCs, the joining of forces between FceRI and MRGPRX2 will allow to orchestrate defense programs more swiftly and efficiently. Skin MCs are ideal to study the collaboration between MRGPRX2 and FceRI as they natively express both receptor networks in physiological ratios. We will explore whether additivity can turn into synergism at low signal strength, assess whether the crosstalk is modulated by the microenvironment, and interrogate cooperation in programs beyond degranulation. Global phosphoproteomics will provide deep insights into the mechanistic underpinnings governing communication between the networks. Combinatorial stimulation greatly expands the number of possible scenarios, in which MCs release mediators causing “allergic” symptoms; it may be the rule rather than exception in vivo. Since MRGPRX2 has hundreds of ligands, both endogenous and exogenous, its function either alone or in tandem with FceRI can explain phenomena that have remained inexplicable for decades with important corollaries for clinical management. Other areas of investigation encompass the degranulation apparatus contracted by MRGPRX2, as well as the distinction between biased (activating either the G protein or the -arrestin module) and balanced ligands (activating both). Moreover, though histamine and proteases were believed to be exocytosed together, there is increasing evidence of selected release. We will therefore explore whether one route prioritizes a certain profile over the other. This is relevant to pruritic dermatoses, in which itch is more commonly dictated by tryptase than histamine. After completion, the project will have substantially advanced our understanding of MRGPRX2 biology, and how it differs from FceRI. We will comprehend the signaling events downstream of MRGPRX2, elaborate differences across ligand types, appreciate the sequelae of MRGPRX2 and FceRI stimulated together, and gain insights into whether MRGPRX2 and FceRI differ in the preferred release of preformed mediators. Collectively, we will have strengthened the perception of MC-dependent disease-promoting processes in the absence of – or in cooperation with – the allergic pathway.

• DFG Programme: Research Grants