A Celiac Cellular Phenotype, with Altered LPP Sub-Cellular Distribution, Is Inducible in Controls by the Toxic Gliadin Peptide P31-43

Merlin Nanayakkara,Luigi Greco,Riccardo Troncone,Alessandra Gaito,Roberta Kosova,Renata Auricchio,Marco Sarno,Maria Vittoria Barone,Giuliana Lania,Martina Galatola,Marialaura Cuomo,Salvatore Auricchio

doi:10.1371/journal.pone.0079763

Merlin Nanayakkara, Luigi Greco + Show 10 more

Open Access

https://doi.org/10.1371/journal.pone.0079763

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Journal: PloS one	Publication Date: Nov 22, 2013
Citations: 58	License type: CC BY 3.0

Affiliation: University of Naples Federico II

Abstract

Celiac disease (CD) is a frequent inflammatory intestinal disease, with a genetic background, caused by gliadin-containing food. Undigested gliadin peptides P31-43 and P57-68 induce innate and adaptive T cell-mediated immune responses, respectively. Alterations in the cell shape and actin cytoskeleton are present in celiac enterocytes, and gliadin peptides induce actin rearrangements in both the CD mucosa and cell lines. Cell shape is maintained by the actin cytoskeleton and focal adhesions, sites of membrane attachment to the extracellular matrix. The locus of the human Lipoma Preferred Partner (LPP) gene was identified as strongly associated with CD using genome-wide association studies (GWAS). The LPP protein plays an important role in focal adhesion architecture and acts as a transcription factor in the nucleus. In this study, we examined the hypothesis that a constitutive alteration of the cell shape and the cytoskeleton, involving LPP, occurs in a cell compartment far from the main inflammation site in CD fibroblasts from skin explants. We analyzed the cell shape, actin organization, focal adhesion number, focal adhesion proteins, LPP sub-cellular distribution and adhesion to fibronectin of fibroblasts obtained from CD patients on a Gluten-Free Diet (GFD) and controls, without and with treatment with A-gliadin peptide P31-43. We observed a “CD cellular phenotype” in these fibroblasts, characterized by an altered cell shape and actin organization, increased number of focal adhesions, and altered intracellular LPP protein distribution. The treatment of controls fibroblasts with gliadin peptide P31-43 mimics the CD cellular phenotype regarding the cell shape, adhesion capacity, focal adhesion number and LPP sub-cellular distribution, suggesting a close association between these alterations and CD pathogenesis.

Highlights

Celiac disease (CD) is characterized by mucosal inflammation due to the Th1 T cell response to certain gliadin peptides [1] and the innate immune response to other gliadin peptides (e.g., A-gliadin peptide P31-43) [2,3]
We described a ‘‘CD cellular phenotype’’ characterized by altered cell shape and actin distribution, increased adhesion structures and proteins, including Lipoma Preferred Partner (LPP), and increased adhesion
The gliadin peptide P31-43 induces the same phenotype in control fibroblasts

Summary

Introduction

Celiac disease (CD) is characterized by mucosal inflammation due to the Th1 T cell response to certain gliadin peptides (e.g., the 33-mer A-gliadin peptide) [1] and the innate immune response to other gliadin peptides (e.g., A-gliadin peptide P31-43) [2,3]. Recent data have shown that gliadin peptides, peptide P31-43, act as growth factors for cell lines, such as CaCo-2, and induce the proliferation of celiac crypt enterocytes [4,5,6]. Because both the 33-mer peptide containing P57-68 [7,8] and the 25-mer peptide containing P31-43 (P31-55) [9] are resistant to hydrolysis by gastric, pancreatic and intestinal proteases, these peptides remain active in vivo in the intestine after gluten ingestion. Gliadin peptides induce cytoskeleton remodeling with altered motility in dendritic cells [20]

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