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Review
, 15 (11), 20518-37

Gliadin Peptides as Triggers of the Proliferative and Stress/Innate Immune Response of the Celiac Small Intestinal Mucosa

Affiliations
Review

Gliadin Peptides as Triggers of the Proliferative and Stress/Innate Immune Response of the Celiac Small Intestinal Mucosa

Maria Vittoria Barone et al. Int J Mol Sci.

Abstract

Celiac disease (CD) is a frequent inflammatory intestinal disease, with a genetic background, caused by gliadin-containing food. Undigested gliadin peptides induce innate and adaptive T cell-mediated immune responses. The major mediator of the stress and innate immune response to gliadin peptides (i.e., peptide 31-43, P31-43) is the cytokine interleukin-15 (IL-15). The role of epithelial growth factor (EGF) as a mediator of enterocyte proliferation and the innate immune response has been described. In this paper, we review the most recent literature on the mechanisms responsible for triggering the up-regulation of these mediators in CD by gliadin peptides. We will discuss the role of P31-43 in enterocyte proliferation, structural changes and the innate immune response in CD mucosa in cooperation with EGF and IL-15, and the mechanism of up-regulation of these mediators related to vesicular trafficking. We will also review the literature that focuses on constitutive alterations of the structure, signalling/proliferation and stress/innate immunity pathways of CD cells. Finally, we will discuss how these pathways can be triggered by gliadin peptide P31-43 in controls, mimicking the celiac cellular phenotype.

Figures

Figure 1
Figure 1
Peptide 31–43 (P31–43) has several effects on cell lines. Schematic representation of the effects of gliadin peptide P31–43 on several cell lines (Caco2, K562, Macrophages). The main effects were grouped in three sets: structural alterations (permeability, actin modifications and alterations in vesicular trafficking), signaling/proliferation (epithelial growth factor/epithelial growth factor receptor- interleukin-15/interleukin-15 receptor-α (EGF/EGFR-IL-15/IL-15R-α) activation, pY-extracellular signal-regulated kinase (pY-ERK)) and stress/innate immunity activation. In all cases there was a quantitative increase in the markers cited, although in the case of actin, the alterations were qualitative. Numbers indicate the bibliographic references.
Figure 2
Figure 2
P31–43 affects cells and biopsies from celiac disease (CD) patients. Schematic representation of the effects of gliadin peptide P31–43 on CD cells and biopsies. The main effects were grouped in three sets: structural alterations (permeability, actin modifications, cell shape and transport/trafficking), signaling/proliferation (EGF/EGFR-IL-15/IL-15R-α activation, pY-ERK) and stress/innate immunity activation as shown. In all cases, there was a quantitative increase in the markers cited, although in the case of actin, the alterations were qualitative. Numbers indicate the bibliographic references. GCD: gluten-containing diet. GFD: gluten-free diet.
Figure 3
Figure 3
(a) Schematic representation of receptor-mediated endocytosis. Trafficking of IL-15R-α, EGFR and transferrin in normal cells. The ligands bind to their receptors on the cell surface. The ligand/receptor complexes are internalized by a process of endocytosis and enter into vesicles “early”. The protein hepatocyte growth factor regulated substrate (HRS) regulates the maturation of endosomes from early to late. If HRS is not properly localized on the membrane of early endosomes, vesicular trafficking is altered. IL-15 and transferrin entering the compartment vesicular recycling are transported to the cell membrane. Receptor tyrosine kinases, such as EGFR, are only partially recycled because their principal destiny is to be transported in the late vesicular compartments to be degraded in lysosomes. When these receptors are in the early compartment, they can still signal within the cell. These transport phenomena within the cell regulate the duration of the activation of the receptors regulating processes essential for cell function, such as activation of innate immunity, cell proliferation, regulation of the actin cytoskeleton, motility and permeability. Alterations in the maturation of endosomes may therefore impair the functionality of the cell in many different ways; and (b) Effect of P31–43 on vesicular trafficking of IL-15R-α, EGFR and transferrin within the cells. The peptide P31–43, due to a sequence homology with HRS, interferes with its correct localization at the level of early endosomes, with a consequent slowing of the maturation of endosomes from early to late, prolonged activation of EGFR, and an increase of transferrin on the cellular membrane and trans-presented IL-15. The main biological consequences at the level of enterocytes of the altered trafficking of these receptors are: Increased proliferation, an alteration in permeability, alterations in the cytoskeleton and cell shape, and an increase in the innate immune response.
Figure 3
Figure 3
(a) Schematic representation of receptor-mediated endocytosis. Trafficking of IL-15R-α, EGFR and transferrin in normal cells. The ligands bind to their receptors on the cell surface. The ligand/receptor complexes are internalized by a process of endocytosis and enter into vesicles “early”. The protein hepatocyte growth factor regulated substrate (HRS) regulates the maturation of endosomes from early to late. If HRS is not properly localized on the membrane of early endosomes, vesicular trafficking is altered. IL-15 and transferrin entering the compartment vesicular recycling are transported to the cell membrane. Receptor tyrosine kinases, such as EGFR, are only partially recycled because their principal destiny is to be transported in the late vesicular compartments to be degraded in lysosomes. When these receptors are in the early compartment, they can still signal within the cell. These transport phenomena within the cell regulate the duration of the activation of the receptors regulating processes essential for cell function, such as activation of innate immunity, cell proliferation, regulation of the actin cytoskeleton, motility and permeability. Alterations in the maturation of endosomes may therefore impair the functionality of the cell in many different ways; and (b) Effect of P31–43 on vesicular trafficking of IL-15R-α, EGFR and transferrin within the cells. The peptide P31–43, due to a sequence homology with HRS, interferes with its correct localization at the level of early endosomes, with a consequent slowing of the maturation of endosomes from early to late, prolonged activation of EGFR, and an increase of transferrin on the cellular membrane and trans-presented IL-15. The main biological consequences at the level of enterocytes of the altered trafficking of these receptors are: Increased proliferation, an alteration in permeability, alterations in the cytoskeleton and cell shape, and an increase in the innate immune response.
Figure 4
Figure 4
Constitutive alterations in cells and biopsies from CD patients. Schematic representation of constitutive alterations of CD cells and biopsies. These alterations have been described in gluten-free diet (GFD) CD patient cells and biopsies. The main constitutive alterations found in GFD CD cells and biopsies were grouped in three sets: Structural alterations (permeability, actin modifications, adhesion), signaling/proliferation (EGF/EGFR activation, NF-κB, pY-ERK) and stress/innate immunity activation as shown. In all cases there was a quantitative increase in the markers cited, although in the case of actin, the alterations were qualitative. Numbers indicate the bibliographic references.
Figure 5
Figure 5
Celiac cellular phenotype induced by gliadin/P31–43 in control cells and biopsies. Schematic representation of the effects of gliadin peptide P31–43 on cells and biopsies from normal subjects. The main effects were grouped in three sets: structural alterations (actin modifications, cell shape, adhesion and cell migration), signaling/proliferation (NF-κB, pY-Fak, pY-paxillin, pY-ERK) and stress/innate immunity activation. In all cases, there was a quantitative increase in the markers cited, although in the case of actin, the alterations were qualitative. Numbers indicate the bibliographic references.

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