MiR-146a Reduces Inflammation in Experimental Pancreatitis via the TRAF6–NF-κB Signaling Pathway in Mice

IF 3.1 4区 医学 Q3 IMMUNOLOGY
Xiaoyu Yang, Yuping Ren, Xueyang Li, Liang Xia, Jianhua Wan
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Abstract

Background

The initial inflammatory response plays a pivotal role in the development of acute pancreatitis. MiR-146a is believed to play a key role in negatively regulating inflammation and potentially contributes to anti-inflammatory activity in acute pancreatitis, though its mechanism remains largely unexplored.

Objectives

This study aimed to explore the effects of miR-146a on AP in mice and clarify its regulatory mechanisms in pancreatic inflammation and damage.

Methods

Adult male BALB/C mice were used. Adeno-associated virus (AAV) vectors were used to modulate miR-146a expression in mice via tail vein injection. AP was induced by intraperitoneal injection of caerulein, caerulein + LPS, or l-arginine. Histological analysis, immunohistochemistry staining, immunofluorescence staining, measurements of amylase and lipase activities, and qRT-PCR were performed.

Results

Overexpression of miR-146a reduced pancreatic damage and inflammation in caerulein-induced AP. It decreased serum amylase and lipase levels, mitigated pathological features such as interstitial edema and inflammatory cell infiltration in the pancreas and lung, and reduced neutrophil infiltration and proinflammatory cytokine expression. MiR-146a attenuated the activation of the NF-κB signaling pathway by inhibiting the degradation of IκBα and the expression of phosphorylated-p65 and reducing the nuclear translocation of NF-κB p65. Similar protective effects of miR-146a were observed in AP models induced by l-arginine and caerulein combined with LPS.

Conclusions

MiR-146a alleviates acute pancreatitis in mice by targeting TRAF6 and suppressing the activation of the NF-κB signaling pathway. These findings suggest that miR-146a could be a potential therapeutic target for AP.

Abstract Image

MiR-146a通过小鼠TRAF6-NF -κB信号通路减轻实验性胰腺炎炎症
背景初始炎症反应在急性胰腺炎的发展中起关键作用。MiR-146a被认为在负性调节炎症中发挥关键作用,并可能有助于急性胰腺炎的抗炎活性,尽管其机制仍未被充分探索。本研究旨在探讨miR-146a对小鼠AP的影响,阐明其在胰腺炎症和损伤中的调节机制。方法采用成年雄性BALB/C小鼠。使用腺相关病毒(AAV)载体通过尾静脉注射调节小鼠miR-146a的表达。通过腹腔注射小蛋白、小蛋白+ LPS或l-精氨酸诱导AP。进行组织学分析、免疫组织化学染色、免疫荧光染色、淀粉酶和脂肪酶活性测定以及qRT-PCR。结果过表达miR-146a可减轻小蛋白诱导AP的胰腺损伤和炎症,降低血清淀粉酶和脂肪酶水平,减轻胰腺和肺间质水肿和炎症细胞浸润等病理特征,降低中性粒细胞浸润和促炎细胞因子表达。MiR-146a通过抑制i -κB α的降解和磷酸化-p65的表达,减少NF-κB p65的核易位,从而减弱NF-κB信号通路的激活。在l-精氨酸和紫蛋白联合LPS诱导的AP模型中,miR-146a也有类似的保护作用。结论MiR-146a通过靶向TRAF6,抑制NF-κB信号通路的激活,减轻小鼠急性胰腺炎。这些发现表明miR-146a可能是AP的潜在治疗靶点。
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来源期刊
Immunity, Inflammation and Disease
Immunity, Inflammation and Disease Medicine-Immunology and Allergy
CiteScore
3.60
自引率
0.00%
发文量
146
审稿时长
8 weeks
期刊介绍: Immunity, Inflammation and Disease is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research across the broad field of immunology. Immunity, Inflammation and Disease gives rapid consideration to papers in all areas of clinical and basic research. The journal is indexed in Medline and the Science Citation Index Expanded (part of Web of Science), among others. It welcomes original work that enhances the understanding of immunology in areas including: • cellular and molecular immunology • clinical immunology • allergy • immunochemistry • immunogenetics • immune signalling • immune development • imaging • mathematical modelling • autoimmunity • transplantation immunology • cancer immunology
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