Apigenin ameliorates inflamed ulcerative colitis by regulating mast cell degranulation via the PAMP-MRGPRX2 feedback loop

https://doi.org/10.1016/j.phymed.2025.156564

Yihan Huang ^a†, Na Wang ^b†, Xiaolan Ji ^a, Shiqiong Luo ^a, Ling Gong ^a, Chenrui Zhao ^a, Guodong Zheng ^a, Rui Liu ^a, Tao Zhang ^a

^aSchool of Pharmacy, Health Science Center, Xi’an Jiaotong University, Xi’an 710061, China

^bDepartment of Otolaryngology, Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, China

Highlights

• MrgprB2-mediated mast cell degranulation is critical for the persistence of inflammation in colitis.
• PAMP-MrgprB2-induced pro-inflammatory positive feedback loop is critical for inflammation.
• Apigenin reduces inflammatory symptoms and improves colon damage and inflammatory cell infiltration.
• Apigenin inhibited degranulation of mast cell and carboxypeptidase A3 levels.
• Apigenin ameliorating ulcerative colitis via MRGPRX2.

Keywords

Ulcerative colitis, Mast cells, Carboxypeptidase A3, Apigenin, MRGPRX2

MrgprX2 regulates mast cell degranulation through PI3K/AKT and PLCγ signaling in pseudo-allergic reactions

https://doi.org/10.1016/j.intimp.2021.108389

Fan Zhang ^ab, Fang Hong ^ab, Lu Wang ^ac, Renjie Fu ^a, Jin Qi ^a, Boyang Yu^ab

^aJiangsu Key Laboratory for TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 21198, China
^bResearch Center for Traceability and Standardization of TCMs, China Pharmaceutical University, Nanjing 211198, China
^cNanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, China

Received 10 August 2021, Revised 27 October 2021, Accepted 9 November 2021, Available online 15 December 2021, Version of Record 15 December 2021.

Highlights

• •MrgprX2 is a key receptor for pseudo-allergic reactions.
• •PI3K/AKT signaling pathway and PLCγ are important downstream of MrgprX2.
• •Inhibiting PI3K/AKT signaling pathway and PLCγ remarkable weakened pseudo-allergic reactions both in vivo and in vitro.

Abstract

The G protein-coupled receptor MrgprX2 in mast cells is known to be a crucial receptor for pseudo-allergic reactions. MrgprX2 activation leads to elevated intracellular calcium levels and mast cell degranulation, but the underlying mechanism remains to be elucidated. Herein, we investigated the role of the phosphatidylinositol 3 kinase (PI3K)/serum-threonine kinase (AKT) signaling pathway and phospholipase C gamma (PLCγ) in mast cell degranulation mediated by MrgprX2 in LAD2 human-derived mast cells. The results showed that phosphorylated AKT (p-AKT) and PLCγ up-regulation were accompanied by an increase in intracellular calcium following activation of MrgprX2 by Compound 48/80, an inducer of mast cell degranulation. In contrast, p-AKT and PLCγ were down-regulated and intracellular calcium levels decreased after MrgprX2 knockdown. Mast cell degranulation was clearly suppressed; however, inhibiting PI3Kand PLCγ phosphorylation did not influence MrgprX2 expression. The increase in calcium concentration was suppressed and mast cell degranulation was weakened. Furthermore, by inhibiting PI3K and PLCγ phosphorylation in animals, the allergic symptoms caused by C48/80 were obviously reduced. We deduced that during the mast cell degranulation observed in pseudoallergic reactions, MrgprX2 regulated intracellular calcium levels via the PI3K/AKT and PLCγ pathways.

Keywords

Pseudo-allergic reactions, Mast cell, MRGPRX2, PI3K/AKT, PLCγ

Inhibitory effect of daphnetin on the C48/80-induced pseudo-allergic reaction

Jingyu Zhang ^a, Ling Hong ^b, Ping Zhang ^a, Yanjie Wang ^a, Tie Hong ^a

https://doi.org/10.1016/j.intimp.2023.110874Get rights and content

Highlights

• Daphnetin inhibits inflammatory mediator release by C48/80-activated RBL-2H3 cells.
• Daphnetin inhibits pseudo-allergic reactions induced by C48/80 in mouse models.
• Daphnetin inhibits C48/80 induced mast cell activation by inhibiting phosphorylation of PLCγ, IP3R, PKC, ERK1/2 and P38.

Abstract

Pseudo-allergic reaction is an allergic reaction mediated by nonimmunoglobulin E (IgE), which does not require prior contact with antigen sensitization and directly leads to mast cell degranulation. Daphnetin (DAP) is known for its anti-inflammatory effects, but there are few studies on the effect of DAP on pseudo-allergy and its mechanism. To investigate the effect of DAP on pseudo-allergy and its mechanism, we inflicted pseudo-allergy on RBL-2H3 cells using C48/80 in vitro. Moreover, to assess the antipseudo-allergy effect of C48/80 in vivo, mouse models of local anaphylaxis, systemic anaphylaxis, and itch were used. The in vitro results show that DAP inhibits degranulation and chemokine release; furthermore, DAP reduced the activation of the PLC-IP3R and MAPK signaling pathways induced by C48/80. Additionally, our in vivo results showed that DAP inhibited C48/80-induced local anaphylaxis and inhibited eosinophil aggregation, vasodilation and mast cell degranulation. In systemic anaphylaxis, DAP inhibits the decrease in body temperature and reduces the release of His, TNF-a and IL-8. In C48/80-induced itch, the number of scratches in mice was reduced. Our results demonstrate that DAP can play a suppressive role in the pseudo-allergy induced by C48/80, providing information for the cure of disorders linked to pseudo-allergic reactions.

Keywords: Pseudo-allergic reaction, Daphnetin,C48/80,RBL-2H3 cells,PLC/IP3R