Potentiation of Epithelial Innate Host Responses by Intercellular Communication

Tamas Dolowschiak,Cécilia Chassin,Sanae Ben Mkaddem,Mathias W Hornef,Thilo M Fuchs,Siegfried Weiss,Alain Vandewalle,Pascale Cossart

doi:10.1371/journal.ppat.1001194

Abstract

The epithelium efficiently attracts immune cells upon infection despite the low number of pathogenic microbes and moderate levels of secreted chemokines per cell. Here we examined whether horizontal intercellular communication between cells may contribute to a coordinated response of the epithelium. Listeria monocytogenes infection, transfection, and microinjection of individual cells within a polarized intestinal epithelial cell layer were performed and activation was determined at the single cell level by fluorescence microscopy and flow cytometry. Surprisingly, chemokine production after L. monocytogenes infection was primarily observed in non-infected epithelial cells despite invasion-dependent cell activation. Whereas horizontal communication was independent of gap junction formation, cytokine secretion, ion fluxes, or nitric oxide synthesis, NADPH oxidase (Nox) 4-dependent oxygen radical formation was required and sufficient to induce indirect epithelial cell activation. This is the first report to describe epithelial cell-cell communication in response to innate immune activation. Epithelial communication facilitates a coordinated infectious host defence at the very early stage of microbial infection.

Highlights

Intestinal epithelial cells line the enteric mucosal surface and provide a physical barrier to maintain the integrity of this vulnerable body surface and prevent invasive infection by luminal microorganisms
The recognition of pathogenic microorganisms results in cell stimulation and the secretion of soluble mediators that attract professional immune cells to the site of infection. This first line host defence works very efficiently despite the often low number of pathogens and the limited amount of mediators secreted per epithelial cell
Using the model of the gut pathogen Listeria monocytogenes and monitoring infection and epithelial activation at a single cell level, we can clearly show that the epithelial response is mainly mediated by non-infected cells

Summary

Introduction

Intestinal epithelial cells line the enteric mucosal surface and provide a physical barrier to maintain the integrity of this vulnerable body surface and prevent invasive infection by luminal microorganisms. Recognition of microbial structures leads to epithelial production of antimicrobial effector molecules and proinflammatory chemoattractive mediators It facilitates an active role in the initiation of the mucosal host response [3,4,5]. The recruitment of professional immune cells to the site of infection occurs within hours and provides a highly efficient dynamic mechanism of the epithelial host defence. It remains unclear, how low number of pathogenic microorganisms as well as the limited spectrum and only moderate amount of chemokine secretion per epithelial cell facilitates stimulation of an effective host defence. We hypothesized that a horizontal intercellular communication between intestinal epithelial cells might help to induce a coordinated epithelial response towards infectious challenge and thereby to amplify the epithelial innate host defence

Methods

Results

Discussion

Conclusion