MRGPRX2 Activation Triggers a Distinct Transcriptional Response That is Enriched in Chronic Spontaneous Urticaria and Atopic Dermatitis Lesions 2251623

Abstract Introduction MRGPRX2 is a mast-cell-specific G protein-coupled receptor that triggers rapid degranulation. Abnormal activation of MRGPRX2 has been implicated in chronic spontaneous urticaria (CSU) and atopic dermatitis (AD). Affected skin shows signs of mast cell degranulation, and endogenous MRGPRX2 agonist levels correlate with disease severity. Evidence for MRGPRX2-driven biology in disease, however, remains limited and motivated further study by transcriptomics. Methods We performed RNA sequencing of the LAD2 human mast cell line after stimulation with MRGPRX2-dependent and -independent agonists. Our analysis focused on identifying transcriptional changes specific to activation with MRGPRX2 agonists, and yielded an MRGPRX2 activation-specific signature. This signature was queried in public CSU and AD bulk and single-cell transcriptomic datasets. Results We identified an MRGPRX2 activation gene signature in LAD2 mast cells, distinct from complement C3a receptor or high-affinity IgE receptor (FcεR)- induced changes, which was validated using qPCR. MRGPRX2 activation signature was enriched specifically and consistently in CSU wheals and AD lesions, but not healthy adjacent skin, in multiple independent datasets. Furthermore, MRGPRX2 activation signature scores correlate with disease severity scores in AD. Conclusion MRGPRX2 activation is enriched in diseased skin from CSU and AD patients, and its inhibition has potential to address unmet clinical need. Funding Source n/a Topic Categories Computational and Systems Immunology (COMP)