MyD88 signaling in dendritic cells and the intestinal epithelium controls immunity against intestinal infection with C. rodentium

Christin Friedrich,Friederike Kruse,Zuobai Wang,Matthias Lochner,Tim Sparwasser,Sophie Thiemann,Till Strowig,Bernhard Holzmann,Panagiota Mamareli,Dario S Zamboni

doi:10.1371/journal.ppat.1006357

Abstract

MyD88-mediated signaling downstream of Toll-like receptors and the IL-1 receptor family is critically involved in the induction of protective host responses upon infections. Although it is known that MyD88-deficient mice are highly susceptible to a wide range of bacterial infections, the cell type-specific contribution of MyD88 in protecting the host against intestinal bacterial infection is only poorly understood. In order to investigate the importance of MyD88 in specific immune and nonimmune cell types during intestinal infection, we employed a novel murine knock-in model for MyD88 that enables the cell type-specific reactivation of functional MyD88 expression in otherwise MyD88-deficient mice. We report here that functional MyD88 signaling in CD11c+ cells was sufficient to activate intestinal dendritic cells (DC) and to induce the early group 3 innate lymphoid cell (ILC3) response as well as the development of colonic Th17/Th1 cells in response to infection with the intestinal pathogen C. rodentium. In contrast, restricting MyD88 signaling to several other cell types, including macrophages (MO), T cells or ILC3 did not induce efficient intestinal immune responses upon infection. However, we observed that the functional expression of MyD88 in intestinal epithelial cells (IEC) also partially protected the mice during intestinal infection, which was associated with enhanced epithelial barrier integrity and increased expression of the antimicrobial peptide RegIIIγ and the acute phase protein SAA1 by epithelial cells. Together, our data suggest that MyD88 signaling in DC and IEC is both essential and sufficient to induce a full spectrum of host responses upon intestinal infection with C. rodentium.

Highlights

The ability to mount specific inflammatory responses is pivotal to the fight against pathogens
Using a novel knock-in mouse model for myeloid differentiation primary response gene 88 (MyD88), we report here that MyD88 signaling in CD11c+ dendritic cells (DC) is sufficient to activate RORγt+ group 3 innate lymphoid cells (ILC3) as well as Th17/Th1 cells in response to infection with C. rodentium
Restricting functional MyD88 signaling to several other immune cell types, including macrophages (MO), T cells and ILC3 did not result in intestinal immunity, while expression of MyD88 in intestinal epithelial cells (IEC) mainly enhanced epithelial barrier integrity

Summary

Introduction

The ability to mount specific inflammatory responses is pivotal to the fight against pathogens. Infection with C. rodentium induces a massive T cell-mediated adaptive response that is necessary to clear the pathogen at the later stages of infection, and causes much of the colonic immunopathology and colitis-like disease symptoms that occur during the infection [8] Both IFN-γ-producing Th1 cells and IL-22-secreting Th22 cells have been reported to be critical effectors of the host response [9,10,11]. A strong Th17 cell response is induced upon infection [12] and mice that lack the Th17 cytokines IL17A/F showed an enhanced susceptibility towards infection with C. rodentium [13] This phenotype was associated with a reduced induction of antimicrobial β-defensins in the colon, suggesting that IL-17 may act mainly by enhancing the intestinal barrier function. Interfering with the proper induction of IL-17/IFN-γ-producing T cells following C. rodentium infection leads to reduced inflammatory pathology in the colon, but at the same time enhances systemic pathogen dissemination and increases mortality, together highlighting the importance of Th17/Th1 cells for both pathogen clearance and the inflammation-associated colitis phenotype [16]

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Results

Discussion

Conclusion