Glaucocalyxin A Attenuates Allergic Responses by Inhibiting Mast Cell Degranulation through p38MAPK/NrF2/HO-1 and HMGB1/TLR4/NF-κB Signaling Pathways.

Yihua Piao,Guanghai Yan,Lianhua Zhu,Liangchang Li,Shan Jin,Jingzhi Jiang,Hongmei Piao,Zhiguang Wang,Chongyang Wang,Li Li,Zhehu Jin,Jih-Huah Wu

doi:10.1155/2021/6644751

Abstract

Glaucocalyxin A (GLA) has various pharmacological effects like antioxidation, immune regulation, and antiatherosclerosis. Here, in this study, the effect and mechanism of GLA on mast cell degranulation were studied. The results of the anti-DNP IgE-mediated passive cutaneous anaphylaxis (PCA) showed that GLA dramatically inhibited PCA in vivo, as evidenced by reduced Evans blue extravasation and decreased ear thickness. In addition, GLA significantly reduced the release of histamine and β-hexosaminidase, calcium influx, cytokine (IL-4, TNF-α, IL-1β, IL-13, and IL-8) production in the RBL-2H3 (rat basophilic leukemia cells), and RPMCs (peritoneal mast cells) in vitro. Moreover, we further investigated the regulatory mechanism of GLA on antigen-induced mast cells by Western blot, which showed that GLA inhibited FcεRI-mediated signal transduction and invalidated the phosphorylation of Syk, Fyn, Lyn, Gab2, and PLC-γ1. In addition, GLA inhibited the recombinant mouse high mobility group protein B1- (HMGB1-) induced mast cell degranulation through limiting nuclear translocation of NF-κBp65. Treatment of mast cells with siRNA-HMGB1 significantly inhibited HMGB1 levels, as well as MyD88 and TLR4, decreased intracellular calcium levels, and suppressed the release of β-hexosaminidase. Meanwhile, GLA increased NrF2 and HO-1 levels by activating p38MAPK phosphorylation. Consequently, these data suggest that GLA regulates the NrF2/HO-1 signaling pathway through p38MAPK phosphorylation and inhibits HMGB1/TLR4/NF-κB signaling pathway to reduce mast cell degranulation and allergic inflammation. Our findings could be used as a promising therapeutic drug against allergic inflammatory disease.

Highlights

Mast cells induce allergic inflammation through the secretion of inflammatory mediators [1], and a variety of cell membrane receptors are expressed on their surface
Glaucocalyxin A (GLA) Inhibits Ear Swelling in passive cutaneous anaphylaxis (PCA) Mice
In order to evaluate the effect of GLA on acute allergic inflammation in vivo, we established a PCA mouse model

Summary

Introduction

Mast cells induce allergic inflammation through the secretion of inflammatory mediators [1], and a variety of cell membrane receptors are expressed on their surface. The combination of IgE and FcεRI and the crosslinking of FcεRI and multivalent antigens cause degranulation of mast cells, which in turn leads to the release of a large number of inflammatory mediators, including secreted granules (containing histamine and proteases), cytokines (such as TNF-α and IL-13), growth factors, and chemokines [2], which potentiate inflammatory immune responses via the secretion of cytokines [3]. Nrf is an important transcription factor in the cap’n’collar family. It is activated when stimulated by oxidative stress and binds to the cis-acting element of the antioxidant response element to initiate the expression of downstream related antioxidant enzymes, such as superoxide dismutase, catalase, and heme. HMGB1 plays an important role in allergic diseases. The role of HMGB1 in mast cells is rarely reported

Methods

Results

Conclusion