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

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The intestinal epithelium consists of a single layer of epithelial cells
that separate the intestinal lumen from the underlying lamina propria. The
single layer of epithelial cells is renewed every 4-5 days and represents the
physical barrier. 158 Pluripotent intestinal
epithelial stem cells permanently self-renew and thus regenerate all lineages
of differentiated intestinal epithelial cells (IECs). 159 All differentiated
IECs migrate from crypt bottoms up along the villus structures and are released
into the luminal space at the villus tips. More than 80% of IECs are absorptive
enterocytes, which are adapted for metabolic and digestive function, and the
remaining 20% are either enteroendocrine cells, goblet cells, microfold cells
(M cells) or Paneth cells. 160 The intestinal
epithelium selectively absorbs dietary nutrients and water, and prevents the
invasion of pathogenic antigens and microbiota. Intestinal barrier selectively
regulates transcellular permeability, which is associated with transporting the
amino acids, ions and SCFAs, 161, 162 microorganisms, and
their molecules in the area between adjacent epithelial cells. 163 The role of the
intestinal barrier involves biochemical, immunological, and physical barrier
functions which maintain the mechanical integrity of the barrier through the
formation of the proteins complex between epithelial cells. The transcellular pathway
requires active
transport mechanisms through selective transporters, pumps and channels
localized on the apical and basolateral plasma membrane. In contrast, the
paracellular pathway is dynamically regulated by an intracellular apical
junctional complex. 164 Desmosomes, adherence
junctions, gap junctions and tight junctions constitute the protein complex in
para-cellular space between epithelial cells (Figure 4). 165, 166 These junctional proteins are important for the permeability of various
molecules and organisms and are linked
to the perijunctional actomyosin ring which is a regulatory factor for
paracellular permeability. 167, 168 Functional and structural
regulation of these junctional proteins is mediated by the contraction of actin
cytoskeleton through the phosphorylation of the myosin light chain in the
epithelial cells. 169 The paracellular
permeability is influenced by intestinal microbiota, their molecules and
cellular specificity, hence the intestinal barrier adapts to physiological and
pathological circumstances. 170, 171Adherence junctional proteins are located under the tight junctions and
formed on the lateral membrane between the epithelial cells and by interactions
between cadherin and catenin superfamilies. 172, 173 Additionally,
adherence junctions also interact with cytoskeleton proteins through the
intracellular adaptor proteins. 174, 175 The role of adherence
junctional proteins such as E-cadherin together with desmosomes is the
mechanical regulation of adjacent cells strength. 176 Interaction between
cadherin and catenin is associated with the maintenance of cell polarity, 177 migration and
homeostasis. 178, 179 Dysregulated E-cadherin
leads to the leaky barrier through light cellular adhesion and the disturbance
of cellular proliferation. 180, 181

Barrier functions in
the intestine are highly related to the complex regulation of tight junctional
proteins. The paracellular pathway for barrier functions is maintained by apical
tight junctional proteins such as claudin, occludin, zonula occludens-1 (ZO-1) and
junctional adhesion molecule (JAM). 182 These proteins are
located between the apical and lateral membrane regions and have a highly
dynamic structure, capable of being constantly remodeled. 168 The transmembrane
proteins such as claudin and occludin are connected to the zonula occludens
family, which is linked with the actin cytoskeleton, in order to regulate
interepithelial permeability of the intestinal barrier. 166, 183 Similar to adherence
junctions, tight junctional proteins regulate cellular polarity, signaling and
vesicle trafficking. 184 Regarding the function
of tight junctional proteins, cleaved occludin increased paracellular
permeability when the allergen DerP1 disrupted occludin through proteolytic
cleavage. 185 However, deletion of
occludin did not result in increased paracellular permeability, 186 suggesting that
disruption of ocludin was independent of compromised barrier function, even
though occludin is an important for the regulation of barrier functions.
Interestingly, phosphorylated occludin led to disrupted ZO-1, resulting in the
impairment of barrier functions. 187 JAM-A deficient mice
demonstrate that JAM-A plays a role in formation and assembly of tight
junctional proteins, and maintenance of barrier integrity. 188 JAM-A-/- mice showed
increased intestinal permeability and susceptibility to DSS colitis, suggesting
that impairment of barrier is closely associated with disease development in
the intestine. 189The gastrointestinal (GI) tract contains the highest amounts of proteases
that activate PARs in the lumen of the intestine. In addition to direct
activation of PARs, the intestinal luminal proteases indirectly engage in
proteolytic cleavage of junctional proteins. 190 PARs consist of 7
transmembrane domain G-protein coupled receptors with 4 identified family
(PAR1~4), 191 and activated by
proteolytic cleavage of N-terminal termini, thereby binding the second loops on
the amino terminus and generates signaling cascades (Figure 5). 192, 193 PARs are present on
epithelial, neuronal and inflammatory cells, 194, 195 and play a role for
intestinal barrier integrity, neuronal activation and immune regulation. 191, 196, 197 Activation of PAR-1, 3
by thrombin and PAR-2 by trypsin analogues are associated with barrier
functions in the intestine. 193, 198 While PAR-1 activation
regulates epithelial and smooth muscle functions in the intestine, PAR-3 and 4
are associated with neutrophil functions rather than epithelial barrier
regulation. 199PAR-2 activation affects epithelial permeability, motility and immune
regulation. 200 Several studies showed
that apical and basolateral activation of PAR-2 mediate different signaling
cascades; apical PAR-2 is activated by trypsin, matriptase and bacterial serine
proteases, 201 while basolateral
activation is induced by cellular tryptase. 202–204 The stimulation of
PAR-2 agonist SLIGRL revealed that PAR-2 activation increases the intestinal
permeability, even though the role of PAR-2 activation between the apical and
basolateral sides is controversial. 205–207 SLIGRL-mediated PAR-2
activation is linked to phosphorylation of the myosin light chain through
myosin light chain kinase, which promotes paracellular permeability. 208 Also, PAR-2 promotes
ERK1/2 activation belonging to the mitogen-activated protein kinases, resulting
in the relocation of tight junctional proteins. 193, 206, 209 PAR-2 activation
contributes to the physiological barrier function as well as disease initiation
such as IBS, IBD and colorectal cancer. 210 PAR-2 deficient mice
demonstrated that PAR-2 activation mediates the intestinal inflammation
associated with colitis development. 203, 211 It is well known that PAR-2 activation is influenced by serine
proteases such as trypsin, and subsequently dysregulates tight junctional
proteins, 203 suggesting that PAR-2 activation breaks down barrier tightness, and
consequently affects intestinal inflammation.

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