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

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 

机构地区：[1]Department of Gastroenterology,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,China [2]Department of Pathology and Pathophysiology,and Department of Gastroenterology at Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,China [3]Immunological Disease Research Center,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,China [4]Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province,Hangzhou,China [5]Department of Pathology and Pathophysiology,Zhejiang University School of Medicine,Hangzhou,China [6]Department of General Medicine,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,China [7]Department of Immunology,Harvard Medical School,Boston,MA,USA [8]Zhejiang Laboratory for Systems and Precision Medicine,Zhejiang University Medical Center,Hangzhou,China

出　　处：《Cellular & Molecular Immunology》2023年第2期119-130,共12页中国免疫学杂志（英文版）

基　　金：supported by the National Natural Science Foundation of China(82271862 and 81873418 to YK,82171730 to PX,81970484 to QC);the Zhejiang Provincial Ten Thousand Program for Leading Talents of Science and Technology Innovation(2021R52015 to YK);the Natural Science Foundation of Zhejiang Province(LY20H160032 to PX,LQ21H090064 to TP).

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-αproduction translationally by reducing the glyceraldehyde 3-phosphate level,thus promoting GAPDH binding to TNF-αmRNA.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.

关 键 词：COLITIS MANNOSE MACROPHAGES Intestinal epithelial cells TNF-ALPHA Endoplasmic reticulum stress 

分 类 号：R574[医药卫生—消化系统]