Deoxynivalenol induces pyroptosis and IL-1β secretion via P2X7R signal in murine RAW264.7 macrophages

IF 2.6 4区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicon Pub Date : 2025-05-15 DOI:10.1016/j.toxicon.2025.108418

Zihui Qin , Huayue Zhang , Jie Zhang , Tushuai Li , Kamil Kuca , Jiaguo Liu , Wenda Wu

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引用次数: 0

Abstract

Deoxynivalenol (DON), a trichothecene mycotoxin, exerts pro-inflammatory and immunomodulatory activity. Interleukin (IL)-1β serves a crucial part as a gate keeper of inflammation in DON-induced macrophages, but an overview of how DON exposure elicits IL-1β secretion from RAW264.7 cells has not been fully illustrated. Here we found that the cellular phenomenon, involved with a type of programmed cell death known as pyroptosis, contains: 1) increase of pro-IL-1β expression, 2) motivation of caspase-1, 3) caspase-1-dependent maturement of IL-1β, 4) caspase-1 fragmentation of gasdermin D (GSDMD), and 5) IL-1β secretion through GSDMD pore. Mechanistically, the present study certified that DON both as first and second signals engaged in IL-1β release is mediated by purinergic P2X7 receptor (P2X7R)-Src signaling. During this process, P2X7R signal is required for GSDMD pore forming course in ASC-independent manner. Moreover, blocking of K⁺ efflux, ROS formation, as well as cathepsin B activity decreases IL-1β export. Our data show that exposure to DON does cause pyroptosis and IL-1β secretion via P2X7R signal in RAW264.7 macrophages. Overall, these results provide new mechanistic clue for DON as a pro-inflammatory factor in innate immune signaling events.

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脱氧雪腐酚醇通过P2X7R信号诱导小鼠RAW264.7巨噬细胞焦亡和IL-1β分泌

脱氧雪腐镰刀菌烯醇（DON）是一种霉菌毒素，具有促炎和免疫调节活性。白细胞介素(IL)-1β在DON诱导的巨噬细胞炎症中起着至关重要的作用，但DON暴露如何诱导RAW264.7细胞分泌IL-1β的概述尚未得到充分说明。在这里，我们发现与一种被称为焦亡的程序性细胞死亡有关的细胞现象包括：1)pro-IL-1β表达增加，2)caspase-1的动机，3)caspase-1依赖性IL-1β成熟，4)caspase-1裂解气皮蛋白D (GSDMD)，以及5)通过GSDMD孔分泌IL-1β。在机制上，本研究证实DON作为参与IL-1β释放的第一和第二信号是通过嘌呤能P2X7受体(P2X7R)-Src信号传导介导的。在此过程中，GSDMD成孔过程需要P2X7R信号，且与asc无关。此外，阻断K+外排、ROS形成以及组织蛋白酶B活性可减少IL-1β的输出。我们的数据表明，暴露于DON确实会引起RAW264.7巨噬细胞的焦亡和通过P2X7R信号分泌IL-1β。总之，这些结果为DON在先天免疫信号事件中作为促炎因子提供了新的机制线索。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicon 医学-毒理学

CiteScore

4.80

自引率

10.70%

发文量

358

审稿时长

68 days

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