PCSK6 Mediates Th1 Differentiation and Promotes Chronic Colitis Progression and Mucosal Barrier Injury Via STAT1

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2023 May 21

PMID 37211384

Authors

Xiaoping Mei

Hongkun Zhou

Zhengwei Song

Xiaodan Yang

Xiaorong Liu

Jianguo Fei

Yiyu Shen

Xiaoguang Wang

Affiliations

Soon will be listed here.

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.

Citing Articles

A self-activated and protective module enhances the preclinical performance of allogeneic anti-CD70 CAR-T cells.

Zhang Z, Zhao L, Huang T, Chen Z, Zhao Y, Liang J Front Immunol. 2025; 15:1531294.

PMID: 39906740 PMC: 11792090. DOI: 10.3389/fimmu.2024.1531294.

References

SWANSON M, Lee W, Sanders V . IFN-gamma production by Th1 cells generated from naive CD4+ T cells exposed to norepinephrine. J Immunol. 2000; 166(1):232-40. DOI: 10.4049/jimmunol.166.1.232. View

Carissimo G, Teo T, Chan Y, Lee C, Lee B, Torres-Ruesta A . controls chikungunya virus-specific pathogenic T cell IFNγ Th1 stimulation in mice. Life Sci Alliance. 2019; 2(1). PMC: 6342136. DOI: 10.26508/lsa.201900298. View

Lee K, Park M, Ji K, Lee H, Jang J, Yoon I . Bacterial β-(1,3)-glucan prevents DSS-induced IBD by restoring the reduced population of regulatory T cells. Immunobiology. 2014; 219(10):802-12. DOI: 10.1016/j.imbio.2014.07.003. View

Trial J, Cieslik K, Haudek S, Duerrschmid C, Entman M . Th1/M1 conversion to th2/m2 responses in models of inflammation lacking cell death stimulates maturation of monocyte precursors to fibroblasts. Front Immunol. 2013; 4:287. PMC: 3776235. DOI: 10.3389/fimmu.2013.00287. View

Kong J, Zhang Z, Musch M, Ning G, Sun J, Hart J . Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am J Physiol Gastrointest Liver Physiol. 2007; 294(1):G208-16. DOI: 10.1152/ajpgi.00398.2007. View

Lee S, Shin S, Lee S, Lee M, Kang T, Noh K . Mycobacterium abscessus MAB2560 induces maturation of dendritic cells via Toll-like receptor 4 and drives Th1 immune response. BMB Rep. 2014; 47(9):512-7. PMC: 4206727. DOI: 10.5483/bmbrep.2014.47.9.001. View

Linterman M, Rigby R, Wong R, Yu D, Brink R, Cannons J . Follicular helper T cells are required for systemic autoimmunity. J Exp Med. 2009; 206(3):561-76. PMC: 2699132. DOI: 10.1084/jem.20081886. View

Diehl S, Rincon M . The two faces of IL-6 on Th1/Th2 differentiation. Mol Immunol. 2002; 39(9):531-6. DOI: 10.1016/s0161-5890(02)00210-9. View

Preusse C, Goebel H, Held J, Wengert O, Scheibe F, Irlbacher K . Immune-mediated necrotizing myopathy is characterized by a specific Th1-M1 polarized immune profile. Am J Pathol. 2012; 181(6):2161-71. DOI: 10.1016/j.ajpath.2012.08.033. View

10.

Dwivedi D, Grin P, Khan M, Prat A, Zhou J, Fox-Robichaud A . Differential Expression of PCSK9 Modulates Infection, Inflammation, and Coagulation in a Murine Model of Sepsis. Shock. 2016; 46(6):672-680. DOI: 10.1097/SHK.0000000000000682. View

11.

Mbikay M, Sirois F, Gyamera-Acheampong C, Wang G, Rippstein P, Chen A . Variable effects of gender and Western diet on lipid and glucose homeostasis in aged PCSK9-deficient C57BL/6 mice CSK9PC57BL/6. J Diabetes. 2014; 7(1):74-84. DOI: 10.1111/1753-0407.12139. View

12.

Testa G, Staurenghi E, Giannelli S, Sottero B, Gargiulo S, Poli G . Up-regulation of PCSK6 by lipid oxidation products: A possible role in atherosclerosis. Biochimie. 2020; 181:191-203. DOI: 10.1016/j.biochi.2020.12.012. View

13.

Steiner D, Thomas M, Hu J, Yang Z, Babiarz J, Allen C . MicroRNA-29 regulates T-box transcription factors and interferon-γ production in helper T cells. Immunity. 2011; 35(2):169-81. PMC: 3361370. DOI: 10.1016/j.immuni.2011.07.009. View

14.

Glueck C, Shah P, Goldenberg N, Prince M, Lee K, Jetty V . 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; 15:55. PMC: 4788934. DOI: 10.1186/s12944-016-0227-2. View

15.

K Au K, Le Page C, Ren R, Meunier L, Clement I, Tyrishkin K . STAT1-associated intratumoural T1 immunity predicts chemotherapy resistance in high-grade serous ovarian cancer. J Pathol Clin Res. 2016; 2(4):259-270. PMC: 5129574. DOI: 10.1002/cjp2.55. View

16.

Pasieka T, Cilloniz C, Lu B, Teal T, Proll S, Katze M . Host responses to wild-type and attenuated herpes simplex virus infection in the absence of Stat1. J Virol. 2008; 83(5):2075-87. PMC: 2643728. DOI: 10.1128/JVI.02007-08. View

17.

Wang F, Wang L, Jiang H, Chang X, Pan J . Inhibition of PCSK6 may play a protective role in the development of rheumatoid arthritis. J Rheumatol. 2014; 42(2):161-9. DOI: 10.3899/jrheum.140435. View

18.

Young D, Lowe L, Booth S, Whitters M, Nicholson L, Kuchroo V . IL-4, IL-10, IL-13, and TGF-beta from an altered peptide ligand-specific Th2 cell clone down-regulate adoptive transfer of experimental autoimmune encephalomyelitis. J Immunol. 2000; 164(7):3563-72. DOI: 10.4049/jimmunol.164.7.3563. View

19.

Gratacos J, Collado A, Filella X, Sanmarti R, Canete J, Llena J . Serum cytokines (IL-6, TNF-alpha, IL-1 beta and IFN-gamma) in ankylosing spondylitis: a close correlation between serum IL-6 and disease activity and severity. Br J Rheumatol. 1994; 33(10):927-31. DOI: 10.1093/rheumatology/33.10.927. View

20.

Burstein H, Shea C, Abbas A . Aqueous antigens induce in vivo tolerance selectively in IL-2- and IFN-gamma-producing (Th1) cells. J Immunol. 1992; 148(12):3687-91. View