IL-22 Increases Permeability of Intestinal Epithelial Tight Junctions by Enhancing Claudin-2 Expression

Abstract

Dysfunction of the epithelial barrier is a hallmark of inflammatory intestinal diseases. The intestinal epithelial barrier is maintained by expression of tight junctions that connect adjacent epithelial cells and seal the paracellular space. IL-22 is critical for the maintenance of intestinal barrier function through promoting antipathogen responses and regeneration of epithelial tissues in the gut. However, little is known about the effects of IL-22 on the regulation of tight junctions in the intestinal epithelium. In this study we report that IL-22 signals exclusively through the basolateral side of polarized Caco-2 cell monolayers. IL-22 treatment does not affect the flux of uncharged macromolecules across cell monolayers but significantly reduces transepithelial electrical resistance (TEER), indicating an increase of paracellular permeability for ions. IL-22 treatment on Caco-2 monolayers and on primary human intestinal epithelium markedly induces the expression of Claudin-2, a cation-channel-forming tight junction protein. Furthermore, treatment of IL-22 in mice upregulates Claudin-2 protein in colonic epithelial cells. Knocking down Claudin-2 expression with small interfering RNA reverses the reduction of TEER in IL-22-treated cells. Moreover, IL-22-mediated upregulation of Claudin-2 and loss of TEER can be suppressed with the treatment of JAK inhibitors. In summary, our results reveal that IL-22 increases intestinal epithelial permeability by upregulating Claudin-2 expression through the JAK/STAT pathway. These results provide novel mechanistic insights into the role of IL-22 in the regulation and maintenance of the intestinal epithelial barrier.

Dynamics of Intestinal Inflammatory Cytokines and Tight Junction Proteins of Turbot (Scophthalmus maximus L.) During the Development and Recovery of Enteritis Induced by Dietary β-Conglycinin

“…Generally, tight junction serves as an important physical barrier to protect the intestine, and the damaged structure of the tight junction could facilitate the invasion of pathogen and pathogenic bacteria from intestinal lumen (Le et al, 2008;Turner, 2009;Sturgeon and Fasano, 2016;Takiishi et al, 2017). Claudins are the major barrier-forming proteins of tight junction structure (Wang Y. et al, 2017). Occludin is essential for some mechanisms of tight junction regulation and responsible for part of the structural function of tight junction (Buckley and Turner, 2017).…”

The role of IL-22 in intestinal health and disease

“…IL-22 has also been implicated in the pathophysiology of diarrhea, a primitive, physical method of disposing of pathogens and toxins by flushing them out of the body. IL-22 stimulation leads to up-regulation of epithelial claudin-2, a key regulatory subunit of epithelial tight junctions, and can thereby elicit water efflux, diarrhea, and pathogen clearance in the intestine (Tsai et al, 2017; Wang et al, 2017b). In humans, claudin-2 and IL-22 are both up-regulated in diseases with increased epithelial barrier permeability, such as inflammatory bowel disease (IBD; Zeissig et al, 2007) and celiac disease (Ong et al, 2019).…”

Zinc Chelation Specifically Inhibits Early Stages of Dengue Virus Replication by Activation of NF-κB and Induction of Antiviral Response in Epithelial Cells

“…We first examined the barrier properties of two epithelial cell lines Caco-2 (colon) and A549 (lung) by growing these cells on transwell inserts for 4 days and measuring the trans-epithelial electrical resistance (TEER) every day. Caco-2 cells have been reported to have higher expression of tight junction proteins and undergo differentiation whereas A549 cells have lower TEER values and do not undergo differentiation (27)(28)(29)(30). As expected, the basal levels of TEER was about 200-fold lower in A549 cells as compared to Caco-2 on day 2, however, both cell lines showed an increase in the TEER values with time in culture and started to plateau by day 4 (Supplementary Figures 1A,B).…”