冷诱导rna结合蛋白通过激活IBS-D中的肥大细胞促进肠道屏障功能障碍和内脏超敏反应。

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-10-06 DOI:10.1016/j.intimp.2025.115640

Tao Wang , Peiwen Yang , Siyuan Dong , Xin He , Fei Dai , Jinhai Wang , Yi Lyu , Rongqian Wu , Jia Zhang

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引用次数: 0

摘要

背景：冷诱导rna结合蛋白（CIRP）与肠道屏障功能和多种免疫反应有关。肥大细胞（MCs）在肠易激综合征（IBS）的发病机制中起着关键作用。然而，CIRP对MCs的调控及其在腹泻主导型肠易激综合征（IBS-D）中的作用尚不清楚。方法：采用醋酸灌肠联合约束应激法（AA/RS）诱导IBS-D小鼠，观察CIRP的表达。为了探讨CIRP对肠道屏障功能、内脏敏感性和MCs活性的直接影响，我们通过灌肠给药重组小鼠CIRP蛋白（rmCIRP）连续14天。随后，成功构建了系统CIRP敲除（CIRP-/-）小鼠，进一步验证了CIRP在IBS-D中的作用。结果：在本研究中，我们发现CIRP在IBS-D小鼠及相应的细胞模型中表达显著升高。外源性CIRP显著加重了肠道屏障功能障碍和内脏过敏，并伴有MCs的激活。相反，CIRP缺乏恢复肠道屏障功能并降低内脏敏感性，这与MCs激活的抑制有关。进一步的实验表明，MCs激活剂C48/80消除了CIRP缺乏对IBS-D小鼠的保护作用。此外，分别抑制TLR4和TRPV1可消除MCs上CIRP的激活。结论：CIRP在IBS-D的病理生理中起重要作用。靶向CIRP可能是治疗IBS-D的一种有希望的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Cold-inducible RNA-binding protein promotes gut barrier dysfunction and visceral hypersensitivity via activating mast cells in IBS-D

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Cold-inducible RNA-binding protein promotes gut barrier dysfunction and visceral hypersensitivity via activating mast cells in IBS-D

Background

Cold-inducible RNA-binding protein (CIRP) is implicated in gut barrier function and various immune responses. Mast cells (MCs) have been found to play a key role in the pathogenesis of irritable bowel syndrome (IBS). However, the regulation of CIRP on MCs and its role in diarrhea predominant-irritable bowel syndrome (IBS-D) remains unclear.

Methods

CIRP expression was evaluated in IBS-D mice, which were induced via acetic acid enema in combination with restraint stress (AA/RS). To explore the direct effect of CIRP on gut barrier function, visceral sensitivity and the activity of MCs, recombinant murine CIRP protein (rmCIRP) was administered via enema for 14 consecutive days. Subsequently, a systematic CIRP knockout (CIRP^−/−) mouse was constructed successfully to further verify the role of CIRP in IBS-D.

Results

In present study, we found the expression of CIRP was significantly increased in IBS-D mice and corresponding cell models. Exogenous CIRP administration significantly exacerbated gut barrier dysfunction and visceral hypersensitivity, which were accompanied by the activation of MCs. Conversely, CIRP deficiency restored gut barrier function and reduced visceral sensitivity, which was associated with the inhibition of MCs activation. Further experiments revealed that C48/80, a MCs activator, eliminated the protective effect of CIRP deficiency in IBS-D mice. In addition, inhibition of TLR4 and TRPV1, respectively, eliminated the activation of CIRP on MCs.

Conclusions

CIRP plays a crucial role in the pathophysiology of IBS-D. Targeting CIRP may represent a promising therapeutic strategy for IBS-D.

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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.