脂联素缺乏通过抑制CXCL13的产生来预防慢性结肠炎相关的结肠纤维化。

Adiponectin deficiency prevents chronic colitis-associated colonic fibrosis via inhibiting CXCL13 production.

作者信息

Xiao Haitao, Xing Tianhang, Qiu Miao, Zhang Guangtao, Yang Gongli, Chen Wenke, Hu Die, Xue Deao, Peng Jiao, Du Bin

机构信息

Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, China; Department of Pharmacy, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, China; Hebei Key Laboratory of Natural Products Activity Components and Function, Hebei Normal University of Science and Technology, Qinhuangdao, Hebei 066004, China.

出版信息

J Adv Res. 2024 Dec 24. doi: 10.1016/j.jare.2024.12.032.

DOI:10.1016/j.jare.2024.12.032

PMID:39725008

Abstract

INTRODUCTION

Colonic fibrosis is a long-term complication of inflammatory bowel disease (IBD), often leading to functional impairment, intestinal obstruction, and surgery. Adiponectin (APN) is an adipokine derived from adipocytes that plays a pleiotropic role in fibrosis regulation, depending on tissue and cell type specific or disease context, but its role in colonic fibrosis remains unclear.

OBJECTIVE

To explore the role and involved mechanism of APN in chronic colitis-associated colonic fibrosis.

METHODS

Studies were performed in GEO database, colonic tissues of UC patients, dextran sulfate sodium (DSS)-induced colonic fibrosis in male wild-type (WT) and APN mice, mouse L929 and human CCD-18Co fibroblasts treated with recombinant CXCL13 protein, and colonic fibrosis in WT mice infected with shRNA of CXCL13.

RESULTS

APN was highly expressed in the colonic tissues of UC patients and positively correlated with the colonoscopy score and colonic fibrosis markers COL1A1 and COL3A1. APN deficiency significantly improved chronic colitis-induced colonic fibrosis in mice with down-regulating collagenase accumulation and expressions of TGF-β, α-SMA, COL1A1, COL3A1, and MMP-9 in colonic tissues. Transcriptomics showed that APN deficiency mainly affected cytokine-cytokine receptor interactions, especially CXCL13 signaling. Follow-up studies showed that APN deficiency significantly decreased the number of colonic F4/80CD206CXCL13 macrophages by weakening Akt phosphorylation. Additional experiments confirmed that CXCL13 notably increased the expressions of α-SMA and COL1A1 in mouse and human fibroblasts by activating p-Akt, p-p38, p-ERK, and p-JNK. Moreover, inhibiting CXCL13 with shRNA significantly ameliorated colonic fibrosis in mice with DSS-induced chronic colitis. Immunohistochemistry analysis revealed high expression of CXCL13 in the colon tissues of patients with UC, showing a positive correlation with APN, COL1A1, and COL3A1.

CONCLUSION

APN contributes to the progression of colonic fibrosis and can exacerbate this condition by regulating the secretion of CXCL13 in the colon, offering potential new perspectives on the pathophysiology of colonic fibrosis.

摘要

引言

结肠纤维化是炎症性肠病（IBD）的一种长期并发症，常导致功能障碍、肠梗阻及手术。脂联素（APN）是一种源自脂肪细胞的脂肪因子，在纤维化调节中发挥多效性作用，其作用取决于组织和细胞类型特异性或疾病背景，但其在结肠纤维化中的作用仍不清楚。

目的

探讨APN在慢性结肠炎相关结肠纤维化中的作用及相关机制。

方法

在基因表达综合数据库（GEO数据库）、溃疡性结肠炎（UC）患者的结肠组织、葡聚糖硫酸钠（DSS）诱导的雄性野生型（WT）和APN基因敲除小鼠的结肠纤维化模型、用重组CXCL13蛋白处理的小鼠L929和人CCD-18Co成纤维细胞，以及感染CXCL13短发夹RNA（shRNA）的WT小鼠的结肠纤维化模型中进行研究。

结果

APN在UC患者的结肠组织中高表达，且与结肠镜检查评分以及结肠纤维化标志物COL1A1和COL3A1呈正相关。APN基因敲除显著改善了小鼠慢性结肠炎诱导的结肠纤维化，下调了结肠组织中胶原酶的积累以及转化生长因子-β（TGF-β）、α-平滑肌肌动蛋白（α-SMA）、COL1A1、COL3A1和基质金属蛋白酶-9（MMP-9）的表达。转录组学显示，APN基因敲除主要影响细胞因子-细胞因子受体相互作用，尤其是CXCL13信号通路。后续研究表明，APN基因敲除通过减弱Akt磷酸化显著减少了结肠F4/80⁺CD206⁺CXCL13⁺巨噬细胞的数量。额外实验证实，CXCL13通过激活p-Akt、p-p38、p-ERK和p-JNK显著增加了小鼠和人成纤维细胞中α-SMA和COL1A1的表达。此外，用shRNA抑制CXCL13可显著改善DSS诱导的慢性结肠炎小鼠的结肠纤维化。免疫组织化学分析显示，CXCL13在UC患者的结肠组织中高表达，与APN、COL1A1和COL3A1呈正相关。