Stabilization of activated mast cells by ORAI1 inhibitor suppresses peanut-induced anaphylaxis and acute diarrhea

Gyeongseo Suk; Do Hoon Kwon; Axel Roers; Soman N Abraham; Hae Woong Choi

doi:10.1016/j.phrs.2023.106887

Stabilization of activated mast cells by ORAI1 inhibitor suppresses peanut-induced anaphylaxis and acute diarrhea

Pharmacol Res. 2023 Oct:196:106887. doi: 10.1016/j.phrs.2023.106887. Epub 2023 Aug 11.

Authors

Gyeongseo Suk¹, Do Hoon Kwon², Axel Roers³, Soman N Abraham⁴, Hae Woong Choi⁵

Affiliations

¹ Division of Life Sciences, Korea University, Seoul 02841, South Korea.
² Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
³ Institute for Immunology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden 01069, Germany.
⁴ Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA; Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA; Molecular Genetics & Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
⁵ Division of Life Sciences, Korea University, Seoul 02841, South Korea. Electronic address: haewoongchoi@korea.ac.kr.

PMID: 37574155
DOI: 10.1016/j.phrs.2023.106887

Abstract

Mast cell (MC) activation triggered by immunoglobulin E (IgE)-antigen crosslinking involves intracellular Ca²⁺ influx through the ORAI1 channel, which precedes granule exteriorization and de novo synthesis of mediators. Pharmacologically suppressing MCs via the inhibition of the ORAI1 Ca²⁺ channel may represent a potential strategy for preventing anaphylaxis. This study demonstrated that peanut-induced anaphylaxis in sensitized mice resulted in significant hypothermia and acute diarrhea. Utilizing the Mcpt5cre-DTA mouse model, we demonstrated that this anaphylactic response was mediated by IgE-antigen-induced MC activation. Prophylactic administration of MC suppressors was an effective means of preventing peanut-induced anaphylaxis. In addition, we observed the potent efficacy of an ORAI1 inhibitor in suppressing the FcεRI-mediated response of murine or human MCs, even when administered concurrently or post-allergen exposure. Mechanistically, the ORAI1 inhibitor was found to prevent the association of Synaptotagmin-2 with the SNARE complex. In an in vivo mouse model of peanut-induced anaphylaxis, the administration of the ORAI1 inhibitor after allergen challenge effectively suppressed allergic acute diarrhea and ameliorated anaphylaxis. Therefore, pharmacological intervention of ORAI1 channel inhibition in MCs represents a promising therapeutic avenue for the treatment of peanut-induced anaphylaxis and acute diarrhea in vivo.

Keywords: Allergy; Anaphylaxis; Mast cell; ORAI1 inhibitor.