Identification of the dog orthologue of human MAS-related G protein coupled receptor X2 (MRGPRX2) essential for drug-induced pseudo-allergic reactions

Eri Hamamura-Yasuno,Yoshimi Tsuchiya,Takuma Iguchi,Kazuyoshi Kumagai,Kazuhiko Mori

doi:10.1038/s41598-020-72819-5

Eri Hamamura-Yasuno, Yoshimi Tsuchiya + Show 3 more

Open Access

https://doi.org/10.1038/s41598-020-72819-5

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Journal: Scientific Reports	Publication Date: Sep 30, 2020
Citations: 15	License type: open-access

Affiliation: Daiichi-Sankyo (Japan)

Abstract

MAS-related G protein coupled receptor-X2 (MRGPRX2), expressed in human mast cells, is associated with drug-induced pseudo-allergic reactions. Dogs are highly susceptible to drug-induced anaphylactoid reactions caused by various drugs; however, the distribution and physiological function of canine MRGPR family genes, including MRGPRX2, remain largely unknown. In the present study, we clarified the distribution of dog MRGPR family genes by real-time quantitative PCR and in situ hybridisation. We also investigated the stimulatory effects of various histamine-releasing agents, including fluoroquinolones, on HEK293 cells transiently transfected with dog MRGPR family genes to identify their physiological function. Dog MRGPRX2 and MRGPRG were distributed in a limited number of tissues, including the skin (from the eyelid, abdomen, and cheek), whereas MRGPRD and MRGPRF were extensively expressed in almost all tissues examined. Histochemical and in situ hybridisation analyses revealed that MRGPRX2 was expressed in dog connective tissue-type mast cells in the skin. Intracellular Ca2+ mobilisation assay revealed that HEK293 cells, expressing dog MRGPRX2 or human MRGPRX2, but not dog MRGPRD, MRGPRF, and MRGPRG, responded to histamine-releasing agents. Our results suggest that dog MRGPRX2 is the functional orthologue of human MRGPRX2 and plays an essential role in drug-induced anaphylactoid reactions in dogs.

Highlights

Pseudo-allergic drug reactions, including injection-site erythema and swelling, are one of the most commonly observed adverse events associated with intravenous administration of drugs, such as fluoroquinolones, antibacterial agents, and peptidergic drugs[1,2]
We confirmed the stimulatory effects of compound 48/80 and several fluoroquinolones on HEK293 cells transiently transfected with dog MRGPR family genes or human MAS-related G protein coupled receptor-X2 (MRGPRX2) to identify the physiological function of dog MRGPR family genes by intracellular C a2+ mobilisation assay
MRGPRX2 was found to be expressed in the kidney and ileum, and MRGPRG was found in the thymus, mesentery, and axillary lymph nodes (Fig. 1)

Summary

Introduction

Pseudo-allergic drug reactions, including injection-site erythema and swelling, are one of the most commonly observed adverse events associated with intravenous administration of drugs, such as fluoroquinolones, antibacterial agents, and peptidergic drugs[1,2]. We investigated the expression of MRGPRX2 in dog mast cells from several tissues by histochemical and in situ hybridisation (ISH) analyses. ISH showed that dog skin mast cells co-expressed c-kit and MRGPRX2, but not MRGPRD, MRGPRF, and MRGPRG (Fig. 2c).

Results

Conclusion