The cells (Figure 4). [165, 166] These

The intestinal epithelium consists of a single layer of epithelial cellsthat separate the intestinal lumen from the underlying lamina propria. Thesingle layer of epithelial cells is renewed every 4-5 days and represents thephysical barrier. 158 Pluripotent intestinalepithelial stem cells permanently self-renew and thus regenerate all lineagesof differentiated intestinal epithelial cells (IECs). 159 All differentiatedIECs migrate from crypt bottoms up along the villus structures and are releasedinto the luminal space at the villus tips. More than 80% of IECs are absorptiveenterocytes, which are adapted for metabolic and digestive function, and theremaining 20% are either enteroendocrine cells, goblet cells, microfold cells(M cells) or Paneth cells. 160 The intestinalepithelium selectively absorbs dietary nutrients and water, and prevents theinvasion of pathogenic antigens and microbiota.

Intestinal barrier selectivelyregulates transcellular permeability, which is associated with transporting theamino acids, ions and SCFAs, 161, 162 microorganisms, andtheir molecules in the area between adjacent epithelial cells. 163 The role of theintestinal barrier involves biochemical, immunological, and physical barrierfunctions which maintain the mechanical integrity of the barrier through theformation of the proteins complex between epithelial cells. The transcellular pathwayrequires activetransport mechanisms through selective transporters, pumps and channelslocalized on the apical and basolateral plasma membrane. In contrast, theparacellular pathway is dynamically regulated by an intracellular apicaljunctional complex. 164 Desmosomes, adherencejunctions, gap junctions and tight junctions constitute the protein complex inpara-cellular space between epithelial cells (Figure 4). 165, 166 These junctional proteins are important for the permeability of variousmolecules and organisms and are linkedto the perijunctional actomyosin ring which is a regulatory factor forparacellular permeability. 167, 168 Functional and structuralregulation of these junctional proteins is mediated by the contraction of actincytoskeleton through the phosphorylation of the myosin light chain in theepithelial cells. 169 The paracellularpermeability is influenced by intestinal microbiota, their molecules andcellular specificity, hence the intestinal barrier adapts to physiological andpathological circumstances.

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170, 171Adherence junctional proteins are located under the tight junctions andformed on the lateral membrane between the epithelial cells and by interactionsbetween cadherin and catenin superfamilies. 172, 173 Additionally,adherence junctions also interact with cytoskeleton proteins through theintracellular adaptor proteins. 174, 175 The role of adherencejunctional proteins such as E-cadherin together with desmosomes is themechanical regulation of adjacent cells strength. 176 Interaction betweencadherin and catenin is associated with the maintenance of cell polarity, 177 migration andhomeostasis.

178, 179 Dysregulated E-cadherinleads to the leaky barrier through light cellular adhesion and the disturbanceof cellular proliferation. 180, 181 Barrier functions inthe intestine are highly related to the complex regulation of tight junctionalproteins. The paracellular pathway for barrier functions is maintained by apicaltight junctional proteins such as claudin, occludin, zonula occludens-1 (ZO-1) andjunctional adhesion molecule (JAM). 182 These proteins arelocated between the apical and lateral membrane regions and have a highlydynamic structure, capable of being constantly remodeled. 168 The transmembraneproteins such as claudin and occludin are connected to the zonula occludensfamily, which is linked with the actin cytoskeleton, in order to regulateinterepithelial permeability of the intestinal barrier. 166, 183 Similar to adherencejunctions, tight junctional proteins regulate cellular polarity, signaling andvesicle trafficking.

184 Regarding the functionof tight junctional proteins, cleaved occludin increased paracellularpermeability when the allergen DerP1 disrupted occludin through proteolyticcleavage. 185 However, deletion ofoccludin did not result in increased paracellular permeability, 186 suggesting thatdisruption of ocludin was independent of compromised barrier function, eventhough occludin is an important for the regulation of barrier functions.Interestingly, phosphorylated occludin led to disrupted ZO-1, resulting in theimpairment of barrier functions. 187 JAM-A deficient micedemonstrate that JAM-A plays a role in formation and assembly of tightjunctional proteins, and maintenance of barrier integrity. 188 JAM-A-/- mice showedincreased intestinal permeability and susceptibility to DSS colitis, suggestingthat impairment of barrier is closely associated with disease development inthe intestine. 189The gastrointestinal (GI) tract contains the highest amounts of proteasesthat activate PARs in the lumen of the intestine.

In addition to directactivation of PARs, the intestinal luminal proteases indirectly engage inproteolytic cleavage of junctional proteins. 190 PARs consist of 7transmembrane domain G-protein coupled receptors with 4 identified family(PAR1~4), 191 and activated byproteolytic cleavage of N-terminal termini, thereby binding the second loops onthe amino terminus and generates signaling cascades (Figure 5). 192, 193 PARs are present onepithelial, neuronal and inflammatory cells, 194, 195 and play a role forintestinal barrier integrity, neuronal activation and immune regulation. 191, 196, 197 Activation of PAR-1, 3by thrombin and PAR-2 by trypsin analogues are associated with barrierfunctions in the intestine. 193, 198 While PAR-1 activationregulates epithelial and smooth muscle functions in the intestine, PAR-3 and 4are associated with neutrophil functions rather than epithelial barrierregulation. 199PAR-2 activation affects epithelial permeability, motility and immuneregulation.

200 Several studies showedthat apical and basolateral activation of PAR-2 mediate different signalingcascades; apical PAR-2 is activated by trypsin, matriptase and bacterial serineproteases, 201 while basolateralactivation is induced by cellular tryptase. 202–204 The stimulation ofPAR-2 agonist SLIGRL revealed that PAR-2 activation increases the intestinalpermeability, even though the role of PAR-2 activation between the apical andbasolateral sides is controversial. 205–207 SLIGRL-mediated PAR-2activation is linked to phosphorylation of the myosin light chain throughmyosin light chain kinase, which promotes paracellular permeability. 208 Also, PAR-2 promotesERK1/2 activation belonging to the mitogen-activated protein kinases, resultingin the relocation of tight junctional proteins. 193, 206, 209 PAR-2 activationcontributes to the physiological barrier function as well as disease initiationsuch as IBS, IBD and colorectal cancer.

210 PAR-2 deficient micedemonstrated that PAR-2 activation mediates the intestinal inflammationassociated with colitis development. 203, 211 It is well known that PAR-2 activation is influenced by serineproteases such as trypsin, and subsequently dysregulates tight junctionalproteins, 203 suggesting that PAR-2 activation breaks down barrier tightness, andconsequently affects intestinal inflammation.


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