Protease inhibitory activity of secretory leukocyte protease inhibitor ameliorates murine experimental colitis by protecting the intestinal epithelial barrier

2021 ◽  
Author(s):  
Sotaro Ozaka ◽  
Akira Sonoda ◽  
Shimpei Ariki ◽  
Naganori Kamiyama ◽  
Shinya Hidano ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Inhibitory Activity ◽  
Experimental Colitis ◽  
Secretory Leukocyte Protease Inhibitor ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Intestinal Epithelial Barrier ◽  
Protease Inhibitory Activity

scholarly journals The Arp2/3 Inhibitory Protein Arpin Is Required for Intestinal Epithelial Barrier Integrity

2021 ◽  
Vol 9 ◽  
Author(s):  
Sandra Chánez-Paredes ◽  
Armando Montoya-García ◽  
Karla F. Castro-Ochoa ◽  
Julio García-Cordero ◽  
Leticia Cedillo-Barrón ◽  
...  
Keyword(s):  
Protein Complexes ◽  
Experimental Colitis ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Intestinal Epithelial Barrier ◽  
Colon Tissue ◽  
Inhibitory Protein ◽  
Α Subunit ◽  
Epithelial Monolayers ◽  
Tnf Α

The intestinal epithelial barrier (IEB) depends on stable interepithelial protein complexes such as tight junctions (TJ), adherens junctions (AJ), and the actin cytoskeleton. During inflammation, the IEB is compromised due to TJ protein internalization and actin remodeling. An important actin regulator is the actin-related protein 2/3 (Arp2/3) complex, which induces actin branching. Activation of Arp2/3 by nucleation-promoting factors is required for the formation of epithelial monolayers, but little is known about the relevance of Arp2/3 inhibition and endogenous Arp2/3 inhibitory proteins for IEB regulation. We found that the recently identified Arp2/3 inhibitory protein arpin was strongly expressed in intestinal epithelial cells. Arpin expression decreased in response to tumor necrosis factor (TNF)α and interferon (IFN)γ treatment, whereas the expression of gadkin and protein interacting with protein C-kinase α-subunit 1 (PICK1), other Arp2/3 inhibitors, remained unchanged. Of note, arpin coprecipitated with the TJ proteins occludin and claudin-1 and the AJ protein E-cadherin. Arpin depletion altered the architecture of both AJ and TJ, increased actin filament content and actomyosin contractility, and significantly increased epithelial permeability, demonstrating that arpin is indeed required for maintaining IEB integrity. During experimental colitis in mice, arpin expression was also decreased. Analyzing colon tissues from ulcerative colitis patients by Western blot, we found different arpin levels with overall no significant changes. However, in acutely inflamed areas, arpin was significantly reduced compared to non-inflamed areas. Importantly, patients receiving mesalazine had significantly higher arpin levels than untreated patients. As arpin depletion (theoretically meaning more active Arp2/3) increased permeability, we wanted to know whether Arp2/3 inhibition would show the opposite. Indeed, the specific Arp2/3 inhibitor CK666 ameliorated TNFα/IFNγ-induced permeability in established Caco-2 monolayers by preventing TJ disruption. CK666 treatment also attenuated colitis development, colon tissue damage, TJ disruption, and permeability in dextran sulphate sodium (DSS)-treated mice. Our results demonstrate that loss of arpin triggers IEB dysfunction during inflammation and that low arpin levels can be considered a novel hallmark of acute inflammation.

scholarly journals Nonmuscle Myosin IIA Regulates Intestinal Epithelial Barrier in vivo and Plays a Protective Role During Experimental Colitis

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Nayden G. Naydenov ◽  
Alex Feygin ◽  
Dongdong Wang ◽  
John F. Kuemmerle ◽  
Gianni Harris ◽  
...  
Keyword(s):  
Experimental Colitis ◽  
Protective Role ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Nonmuscle Myosin ◽  
Intestinal Epithelial Barrier ◽  
Myosin Iia

scholarly journals DHA protects against experimental colitis in IL-10-deficient mice associated with the modulation of intestinal epithelial barrier function

2015 ◽  
Vol 114 (2) ◽  
pp. 181-188 ◽  
Author(s):  
Jie Zhao ◽  
Peiliang Shi ◽  
Ye Sun ◽  
Jing Sun ◽  
Jian-Ning Dong ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Experimental Colitis ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Intestinal Epithelial Barrier ◽  
Epithelial Barrier Function ◽  
Deficient Mice ◽  
Pro Inflammatory Cytokines

A defect in the intestinal barrier is one of the characteristics of Crohn's disease (CD). The tight junction (TJ) changes and death of epithelial cells caused by intestinal inflammation play an important role in the development of CD. DHA, a long-chain PUFA, has been shown to be helpful in treating inflammatory bowel disease in experimental models by inhibiting the NF-κB pathway. The present study aimed at investigating the specific effect of DHA on the intestinal barrier function in IL-10-deficient mice. IL-10-deficient mice (IL-10− / −) at 16 weeks of age with established colitis were treated with DHA (i.g. 35·5 mg/kg per d) for 2 weeks. The severity of their colitis, levels of pro-inflammatory cytokines, epithelial gene expression, the distributions of TJ proteins (occludin and zona occludens (ZO)-1), and epithelial apoptosis in the proximal colon were measured at the end of the experiment. DHA treatment attenuated the established colitis and was associated with reduced infiltration of inflammatory cells in the colonic mucosa, lower mean histological scores and decreased levels of pro-inflammatory cytokines (IL-17, TNF-α and interferon-γ). Moreover, enhanced barrier function was observed in the DHA-treated mice that resulted from attenuated colonic permeability, rescued expression and corrected distributions of occludin and ZO-1. The results of the present study indicate that DHA therapy may ameliorate experimental colitis in IL-10− / − mice by improving the intestinal epithelial barrier function.

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