Inflamed Ulcerative Colitis Regions Associated With MRGPRX2-Mediated Mast Cell Degranulation and Cell Activation Modules, Defining a New Therapeutic Target

Ernie Chen, Ling shiang Chuang, Mamta Giri, Nicole Villaverde, Nai yun Hsu, Ksenija Sabic, Sari Joshowitz, Kyle Gettler, Shikha Nayar, Zhi Chai, Isaac L. Alter, Colleen C. Chasteau, Ujunwa M. Korie, Siarhei Dzedzik, Tin Htwe Thin, Aayushee Jain, Arden Moscati, Gerardus Bongers, Richard H. Duerr, Mark S. SilverbergSteven R. Brant, John D. Rioux, Inga Peter, L. Philip Schumm, Talin Haritunians, Dermot P. McGovern, Yuval Itan, Judy H. Cho

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


Background & Aims: Recent literature has implicated a key role for mast cells in murine models of colonic inflammation, but their role in human ulcerative colitis (UC) is not well established. A major advance has been the identification of mrgprb2 (human orthologue, MRGPX2) as mediating IgE-independent mast cell activation. We sought to define mechanisms of mast cell activation and MRGPRX2 in human UC. Methods: Colon tissues were collected from patients with UC for bulk RNA sequencing and lamina propria cells were isolated for MRGPRX2 activation studies and single-cell RNA sequencing. Genetic association of all protein-altering G-protein coupled receptor single-nucleotide polymorphism was performed in an Ashkenazi Jewish UC case-control cohort. Variants of MRGPRX2 were transfected into Chinese hamster ovary (CHO) and human mast cell (HMC) 1.1 cells to detect genotype-dependent effects on β-arrestin recruitment, IP-1 accumulation, and phosphorylated extracellular signal–regulated kinase. Results: Mast cell-specific mediators and adrenomedullin (proteolytic precursor of PAMP-12, an MRGPRX2 agonist) are up-regulated in inflamed compared to uninflamed UC. MRGPRX2 stimulation induces carboxypeptidase secretion from inflamed UC. Of all protein-altering GPCR alleles, a unique variant of MRGPRX2, Asn62Ser, was most associated with and was bioinformatically predicted to alter arrestin recruitment. We validated that the UC protective serine allele enhances β-arrestin recruitment, decreases IP-1, and increases phosphorylated extracellular signal–regulated kinase with MRGPRX2 agonists. Single-cell RNA sequencing defines that adrenomedullin is expressed by activated fibroblasts and epithelial cells and that interferon gamma is a key upstream regulator of mast cell gene expression. Conclusion: Inflamed UC regions are distinguished by MRGPRX2-mediated activation of mast cells, with decreased activation observed with a UC-protective genetic variant. These results define cell modules of UC activation and a new therapeutic target.

Original languageEnglish
Pages (from-to)1709-1724
Number of pages16
Issue number5
StatePublished - Apr 2021


  • G-Protein Coupled Receptors
  • Mast Cells
  • Single Cell Sequencing
  • Ulcerative Colitis


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