Fisetin alleviates chronic urticaria by inhibiting mast cell activation via MRGPRX2

Abstract

Objectives The activation of mast cell (MC) plays an important part in the pathogenesis of chronic urticaria (CU), and the expression of MRGPRX2 (Mas-related G-protein coupled receptor X2) and the circulating levels of SP (substance P) in skin MC of CU patients increased. Fisetin is a natural flavonoid with anti-inflammatory and antiallergic pharmacological effects. This study aimed to investigate the inhibitory effect of fisetin on CU via MRGPRX2 and its possible molecular mechanisms. Methods OVA/SP co-stimulated and SP-stimulated CU like murine models were used to evaluate the effect of fisetin on CU. MRGPRX2/HEK293 cells and LAD2 cells were used to perform the antagonism effect of fisetin on MC via MRGPRX2. Key findings The results indicated that fisetin prevented urticaria-like symptoms in murine CU models, and inhibited MCs activation by suppressing calcium mobilization and degranulation of cytokines and chemokines via binding to MRGPRX2. The bioinformatics analysis showed that fisetin might have an interaction relationship with Akt in CU. The western blotting experiments showed that fisetin downregulated the phosphorylation levels of Akt, P38, NF-κB, and PLCγ in C48/80 activated LAD2 cells. Conclusions Fisetin alleviates CU progression by inhibiting mast cell activation via MRGPRX2, which may be a novel therapeutic candidate for CU.

Modulation of the Mas-Related G Protein-Coupled Receptor X2 (MRGPRX2) by Xenobiotic Compounds and Its Relevance to Human Diseases

“…Exogenous ligands of MRGPRX2 include the cationic polymer compound 48/80 (C48/80), which is commonly used in receptor functional assays, and a variety of drugs approved by the Food and Drug Administration (FDA), such as fluoroquinolones (e.g., ciprofloxacin), neuromuscular blocking agents (e.g., rocuronium, atracurium), opioids (e.g., morphine), and many others [ 4 , 9 , 28 ]. MRGPRX2 can also be activated or inhibited by other exogenous agents, such as bacterial quorum sensing proteins, insect venoms [ 3 , 29 , 30 ], or many different plant xenobiotics ( Figure 1 ) [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ]; representatives of which are described in the following part of this review.…”

“…Several flavonoids have been identified as potential MRGPRX2 antagonists ( Figure 1 ). Most of them have been reported to have protective effects against hypersensitivity reactions and other health conditions such as pruritus [ 56 ] or CU [ 42 , 132 ]. Additionally, agonists of MRGPRX2 among flavonoids have also been identified [ 33 , 133 ].…”

“…Additionally, agonists of MRGPRX2 among flavonoids have also been identified [ 33 , 133 ]. Flavonoids have been reported to affect MC stimulation both by direct binding to the receptor and by interactions with regulatory enzymes or transcription factors [ 42 , 132 , 134 , 135 ]. In this section, we describe a few representatives of flavonoids that may interact directly with MRGPRX2.…”

“…It has been reported to inhibit several signalling pathways in vitro, including PI3K-Akt-mTOR, P38, and NF-κB [ 142 , 143 ], which were associated with an inhibitory effect in human inflammatory skin models [ 144 ]. Recent research on the SP and ovalbumin co-stimulated CU mouse model demonstrated protective effects of fisetin against CU [ 42 ]. The compound alleviated the symptoms associated with CU in mice and reduced serum levels of inflammatory mediators such as histamine and TNFα, as well as the infiltration of red blood cells into the tissue and degranulation of skin MCs [ 42 ].…”

“…Recent research on the SP and ovalbumin co-stimulated CU mouse model demonstrated protective effects of fisetin against CU [ 42 ]. The compound alleviated the symptoms associated with CU in mice and reduced serum levels of inflammatory mediators such as histamine and TNFα, as well as the infiltration of red blood cells into the tissue and degranulation of skin MCs [ 42 ]. Additionally, fisetin suppressed local and systemic anaphylactoid reactions in mice [ 42 ].…”