Mannose metabolism normalizes gut homeostasis by blocking the TNF-α-mediated proinflammatory circuit

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外文摘要：Mannose is a naturally occurring sugar widely consumed in the daily diet;however,mechanistic insights into how mannose metabolism affects intestinal inflammation remain lacking.Herein,we reported that mannose supplementation ameliorated colitis development and promoted colitis recovery.Macrophage-secreted inflammatory cytokines,particularly TNF-α,induced pathological endoplasmic reticulum stress(ERS)in intestinal epithelial cells(IECs),which was prevented by mannose via normalization of protein N-glycosylation.By preserving epithelial integrity,mannose reduced the inflammatory activation of colonic macrophages.On the other hand,mannose directly suppressed macrophage TNF-α production translationally by reducing the glyceraldehyde 3-phosphate level,thus promoting GAPDH binding to TNF-α mRNA.Additionally,we found dysregulated mannose metabolism in the colonic mucosa of patients with inflammatory bowel disease.Finally,we revealed that activating PMM2 activity with epalrestat,a clinically approved drug for the treatment of diabetic neuropathy,elicited further sensitization to the therapeutic effect of mannose.Therefore,mannose metabolism prevents TNF-α-mediated pathogenic crosstalk between IECs and intestinal macrophages,thereby normalizing aberrant immunometabolism in the gut.

外文关键词：

ColitisMannoseMacrophagesIntestinal epithelial cellsTNF-alphaEndoplasmic reticulum stress

作者：

Peng Xiao、Ziwei Hu、Jiaheng Lang、Tianyuan Pan、Randall Tyler Mertens、Huilun Zhang、Ke Guo、Manlu Shen、Hongqiang Cheng、Xue Zhang、Qian Cao、Yuehai Ke

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作者单位：

Department of Gastroenterology,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,China

Department of Pathology and Pathophysiology,and Department of Gastroenterology at Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,China

Immunological Disease Research Center,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,China

Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province,Hangzhou,China

Department of Pathology and Pathophysiology,Zhejiang University School of Medicine,Hangzhou,China

Department of General Medicine,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,China

Department of Immunology,Harvard Medical School,Boston,MA,USA

Zhejiang Laboratory for Systems and Precision Medicine,Zhejiang University Medical Center,Hangzhou,China

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基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaZhejiang Provincial Ten Thousand Program for Leading Talents of Science and Technology InnovationNatural Science Foundation of Zhejiang ProvinceNatural Science Foundation of Zhejiang Province

项目编号：

822718628187341882171730819704842021R52015LY20H160032LQ21H090064

出版年：

2023

DOI：

10.1038/s41423-022-00955-1

中国免疫学杂志(英文版)

中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI

影响因子：0.731

ISSN：1672-7681

年,卷(期)：2023.20(2)

参考文献量30