Amphotericin B, a polyene macrolide antifungal agent, still plays an important role in the management of serious systemic fungal infections. Amphotericin B deoxycholate (AmBd) has been used to treat invasive fungal infections for over 60 years and remains the primary clinical formulation currently available. Anaphylactoid reactions triggered by AmBd in the clinic have been documented. However, the molecular and cellular events contributing to these reactions have not been clearly elucidated to date. This study demonstrates that the human Mas-related G protein-coupled receptor X2 (MRGPRX2) is the receptor that mediates these anaphylactoid responses. Molecular docking and cellular thermal shift assay (CETSA) indicate that AmBd exhibits potential affinity with MRGPRX2. In vitro, exposure to AmBd results in significant release of LAD2 mast cell granules and induces intracellular Ca mobilization as well as activation of PLC-γ/IP3R and PI3K/AKT signaling pathways. However, these phenomena are reduced in MRGPRX2-knockdown LAD2 cells. In vivo, AmBd triggers paw swelling and a rapid drop in core body temperature in wild-type (WT) mice. However, these reactions are almost absent in MRGPRB2 (the mouse homolog of MRGPRX2) knockout mice (MRGPRB2, MUT). The above results suggest that AmBd activates PLC-γ/IP3R and PI3K/AKT signaling via MRGPRX2 (in human LAD2 mast cells) or MRGPRB2 (in mice), leading to the release of mast cell granules and subsequent triggering of pseudo-allergic reactions. Taken together, this study clarifies the role of MRGPRX2 in triggering pseudo-allergic reactions to AmBd and suggests that MRGPRX2 could be a potential therapeutic target for controlling these reactions.
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http://dx.doi.org/10.1007/s12026-024-09532-2 | DOI Listing |
J Immunotoxicol
December 2024
Department of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, USA.
Cetylpyridinium chloride (CPC) is a quaternary ammonium antimicrobial used in numerous personal care products, human food, cosmetic products, and cleaning solutions. Yet, there is minimal published data on CPC effects on eukaryotes, immune signaling, and human health. Previously, it was shown that low-micromolar CPC inhibits rat mast cell function by inhibiting antigen (Ag)-stimulated Ca mobilization, microtubule polymerization, and degranulation.
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Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
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Institute of Allergology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology, Berlin, Germany. Electronic address:
J Inflamm Res
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College of Pharmacy, Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China.
Immunol Lett
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Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China. Electronic address:
Mas-related G protein-coupled receptor X2 (MRGPRX2) is a newly identified receptor on mast cells that contribute to IgE-independent pseudo-allergy. Ursolic acid (UA), a pentacyclic triterpenoid, has been reported for its anti-allergy effects. However, the protective mechanism against pseudo-allergic reactions remains unclear.
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