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PCSK6 通过 STAT1 介导 Th1 分化，并促进慢性结肠炎的进展和黏膜屏障损伤。

PCSK6 mediates Th1 differentiation and promotes chronic colitis progression and mucosal barrier injury via STAT1.

机构信息

Department of Surgery, Affiliated Hospital of Jiaxing University, Jiaxing 314000, Zhejiang, People’s Republic of China.

Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, Zhejiang, People’s Republic of China.

出版信息

Aging (Albany NY). 2023 May 20;15(10):4363-4373. doi: 10.18632/aging.204739.

DOI:10.18632/aging.204739
PMID:37211384
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10258034/
Abstract

This study was aimed at investigating the expression and role of proprotein convertase subtilisin/kexin type (PCSK6) in inflammatory bowel disease (IBD). DSS induced mouse colitis and mucosal barrier injury, down-regulation of TJ proteins, improvement of permeability, and increases of the proportions of Th1 and M1 macrophages. After PCSK6 knockdown, the colitis in KO mice was improved relative to WT mice, the TJ protein levels increased, and the proportions of Th1 and M1 macrophages decreased. STAT1 inhibitor treatment also inhibited chronic colitis in mice. As revealed by experiments, PCSK6 overexpression promoted the transformation of Th0 into Th1, while PCSK6 silencing suppressed the transfection. COPI assay results revealed the presence of targeted binding relation between PCSK6 and STAT1. PCSK6 binds to STAT1 to promote STAT1 phosphorylation and regulate Th1 cell differentiation, thus promoting the M1 polarization of macrophages and aggravating colitis progression. PCSK6 is promising as the new target for the treatment of colitis.

摘要

本研究旨在探讨前蛋白转化酶枯草溶菌素/克氏蛋白酶 6（PCSK6）在炎症性肠病（IBD）中的表达和作用。DSS 诱导的小鼠结肠炎和黏膜屏障损伤，TJ 蛋白下调，通透性增加，Th1 和 M1 巨噬细胞比例增加。PCSK6 敲低后，KO 小鼠的结肠炎较 WT 小鼠改善，TJ 蛋白水平增加，Th1 和 M1 巨噬细胞比例减少。STAT1 抑制剂治疗也抑制了小鼠的慢性结肠炎。实验表明，PCSK6 过表达促进 Th0 向 Th1 的转化，而 PCSK6 沉默抑制转染。COPI 实验结果显示 PCSK6 和 STAT1 之间存在靶向结合关系。PCSK6 与 STAT1 结合，促进 STAT1 磷酸化，调节 Th1 细胞分化，从而促进巨噬细胞 M1 极化，加重结肠炎进展。PCSK6 有望成为治疗结肠炎的新靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc4e/10258034/4b7312e5a3a8/aging-15-204739-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc4e/10258034/54cafe47cb0a/aging-15-204739-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc4e/10258034/ea8b6b09acae/aging-15-204739-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc4e/10258034/db53520b4c4c/aging-15-204739-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc4e/10258034/536def614956/aging-15-204739-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc4e/10258034/4b7312e5a3a8/aging-15-204739-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc4e/10258034/54cafe47cb0a/aging-15-204739-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc4e/10258034/ea8b6b09acae/aging-15-204739-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc4e/10258034/db53520b4c4c/aging-15-204739-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc4e/10258034/536def614956/aging-15-204739-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc4e/10258034/4b7312e5a3a8/aging-15-204739-g005.jpg

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本文引用的文献

[1]
Acupoint Autohemotherapy Attenuates Atopic Dermatitis Lesions by Regulating Th1/Th2 Balance in DNCB-Induced BALB/c Mice.

Chin J Integr Med. 2022-7

[2]
Up-regulation of PCSK6 by lipid oxidation products: A possible role in atherosclerosis.

Biochimie. 2021-2

[3]
controls chikungunya virus-specific pathogenic T cell IFNγ Th1 stimulation in mice.

Life Sci Alliance. 2019-1-21

[4]
STAT1-associated intratumoural T1 immunity predicts chemotherapy resistance in high-grade serous ovarian cancer.

J Pathol Clin Res. 2016-9-19

[5]
Differential Expression of PCSK9 Modulates Infection, Inflammation, and Coagulation in a Murine Model of Sepsis.

Shock. 2016-12

[6]
Eligibility for PCSK9 treatment in 734 Hypercholesterolemic patients referred to a regional cholesterol treatment center with LDL cholesterol ≥ 70 mg/dl despite maximal tolerated cholesterol lowering therapy.

Lipids Health Dis. 2016-3-12

[7]
Tumor-associated macrophages in oral premalignant lesions coexpress CD163 and STAT1 in a Th1-dominated microenvironment.

BMC Cancer. 2015-8-5

[8]
Inhibition of PCSK6 may play a protective role in the development of rheumatoid arthritis.

J Rheumatol. 2015-2

[9]
Bacterial β-(1,3)-glucan prevents DSS-induced IBD by restoring the reduced population of regulatory T cells.

Immunobiology. 2014-10

[10]
Mycobacterium abscessus MAB2560 induces maturation of dendritic cells via Toll-like receptor 4 and drives Th1 immune response.

BMB Rep. 2014-9

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