Pregnane X receptor activation attenuates intestinal inflammation: The role of pyroptosis and necroptosis inhibition

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-10-04 DOI:10.1016/j.intimp.2025.115620

Yuwei Zheng , Chunyu Qiao , Wanzhe Xiao , Bingxue Liu , Wenyuan Long , Jiexing Zhang , Shuai Lian , Xuming Deng , Hongming Lv

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引用次数: 0

Abstract

Intestinal inflammation compromises epithelial barrier integrity and disrupts immunological homeostasis, escalating the risk of severe gastrointestinal disorders. The Pregnane X Receptor (PXR), a xenobiotic-sensing nuclear receptor, is critical for maintaining intestinal structural integrity and suppressing inflammation, although its mechanistic underpinnings remain poorly characterized. In this study, we explored the therapeutic potential of PCN, a PXR agonist, in mitigating intestinal inflammation using two models: enterohaemorrhagic Escherichia coli O157:H7 (EHEC)-infected mice and lipopolysaccharide (LPS)-stimulated intestinal epithelial cells. PCN administration significantly improved survival rates in EHEC-challenged mice, alleviated intestinal mucosal damage, and restored tight junction protein (ZO-1 and occludin) expression. Concurrently, PCN attenuated Paneth cell dysfunction, macrophage hyperactivation, and pro-inflammatory mediator release (e.g., TNF-α, IL-6). In vitro, PCN counteracted LPS-induced barrier disruption and inflammation by suppressing the TLR4/NF-κB/MAPK axis and downstream pyroptotic (NLRP3/caspase-1/GSDMD), and necroptotic (RIPK1/RIPK3/MLKL) signaling cascades. Interestingly, both EHEC infection and LPS stimulation impaired PCN-driven PXR activation. While PCN rescued EHEC-induced mortality, histological damage, and barrier dysfunction in wild-type mice, its protective effects were markedly diminished in PXR-knockout (PXR^−/−) mice. Furthermore, PXR silencing in cultured cells abolished PCN-mediated inhibition of NF-κB, NLRP3 inflammasome, and necroptosis pathways. These results demonstrate that PXR activation coordinately blocks pyroptosis and necroptosis by modulating the TLR4/NF-κB/MAPK-NLRP3/caspase-1/GSDMD-RIPK1/RIPK3/MLKL axis, thereby preserving intestinal homeostasis. This dual-pathway targeting positions PXR as a promising therapeutic candidate for inflammatory bowel diseases.

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孕烷X受体激活减轻肠道炎症：焦亡和坏死抑制的作用。

肠道炎症损害上皮屏障的完整性，破坏免疫稳态，增加严重胃肠道疾病的风险。妊娠烷X受体（PXR）是一种外源性感知核受体，对维持肠道结构完整性和抑制炎症至关重要，尽管其机制基础尚不清楚。在这项研究中，我们利用肠出血性大肠杆菌O157:H7 （EHEC）感染小鼠和脂多糖（LPS）刺激的肠上皮细胞两种模型，探索了PXR激动剂PCN在缓解肠道炎症方面的治疗潜力。PCN可显著提高ehec小鼠的存活率，减轻肠黏膜损伤，恢复紧密连接蛋白（ZO-1和occludin）的表达。同时，PCN减轻了Paneth细胞功能障碍、巨噬细胞过度活化和促炎介质释放（如TNF-α、IL-6）。在体外，PCN通过抑制TLR4/NF-κB/MAPK轴和下游的焦亡（NLRP3/caspase-1/GSDMD）和坏死（RIPK1/RIPK3/MLKL）信号级联来抵消lps诱导的屏障破坏和炎症。有趣的是，肠出血性大肠杆菌感染和LPS刺激都破坏了pcn驱动的PXR激活。虽然PCN在野生型小鼠中挽救了ehec诱导的死亡、组织学损伤和屏障功能障碍，但在PXR敲除（PXR-/-）小鼠中，PCN的保护作用明显减弱。此外，PXR在培养细胞中的沉默消除了pcn介导的NF-κB、NLRP3炎性体和坏死坏死途径的抑制。这些结果表明，PXR的激活通过调节TLR4/NF-κB/MAPK-NLRP3/caspase-1/GSDMD-RIPK1/RIPK3/MLKL轴协同阻断焦亡和坏死，从而维持肠道内稳态。这种双通路靶向使PXR成为炎症性肠病的有希望的治疗候选药物。

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

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.