Enterocytes, fibroblasts and myeloid cells synergize in anti-bacterial and anti-viral pathways with IL22 as the central cytokine

Jean Paul Ten Klooster,Saertje Verkoeijen,Marianne Bol-Schoenmakers,Kitty Van Summeren,Raymond Pieters,Cornelis A M De Haan,Frank J M Van Kuppeveld,Arno L W Van Vliet

doi:10.1038/s42003-021-02176-0

Jean Paul Ten Klooster, Saertje Verkoeijen + Show 6 more

Open Access

https://doi.org/10.1038/s42003-021-02176-0

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Abstract

IL22 is an important cytokine involved in the intestinal defense mechanisms against microbiome. By using ileum-derived organoids, we show that the expression of anti-microbial peptides (AMPs) and anti-viral peptides (AVPs) can be induced by IL22. In addition, we identified a bacterial and a viral route, both leading to IL22 production by T cells, but via different pathways. Bacterial products, such as LPS, induce enterocyte-secreted SAA1, which triggers the secretion of IL6 in fibroblasts, and subsequently IL22 in T cells. This IL22 induction can then be enhanced by macrophage-derived TNFα in two ways: by enhancing the responsiveness of T cells to IL6 and by increasing the expression of IL6 by fibroblasts. Viral infections of intestinal cells induce IFNβ1 and subsequently IL7. IFNβ1 can induce the expression of IL6 in fibroblasts and the combined activity of IL6 and IL7 can then induce IL22 expression in T cells. We also show that IL22 reduces the expression of viral entry receptors (e.g. ACE2, TMPRSS2, DPP4, CD46 and TNFRSF14), increases the expression of anti-viral proteins (e.g. RSAD2, AOS, ISG20 and Mx1) and, consequently, reduces the viral infection of neighboring cells. Overall, our data indicates that IL22 contributes to the innate responses against both bacteria and viruses.

Highlights

IL22 is an important cytokine involved in the intestinal defense mechanisms against microbiome
In agreement with IL6 being present in 3T3 cultures after hSAA1 or IL1α exposure, we only found IL22 secretion in EL4 cells that were exposed to supernatants from fibroblasts or fibroblast/macrophage co-cultures stimulated with hSAA1 (Fig. 6h), which could be blocked by an inhibitory anti-IL6 antibody (Fig. 6i)
In this paper, we show for the first time that different immune cascades, providing crosstalk between enterocytes, macrophages, dendritic cells, fibroblasts, and T cells, are involved in the induction of IL22 in response to bacterial or viral infections (Fig. 8)

Summary

Introduction

IL22 is an important cytokine involved in the intestinal defense mechanisms against microbiome. We identified a bacterial and a viral route, both leading to IL22 production by T cells, but via different pathways Bacterial products, such as LPS, induce enterocyte-secreted SAA1, which triggers the secretion of IL6 in fibroblasts, and subsequently IL22 in T cells. This IL22 induction can be enhanced by macrophage-derived TNFα in two ways: by enhancing the responsiveness of T cells to IL6 and by increasing the expression of IL6 by fibroblasts. Serum Amyloid A3 (SAA3) are involved in the induction of IL22 in T cells of different origin[5,6,7,8] These cytokines can be induced in myeloid cells, such as macrophages and dendritic cells (DC) by LPS9, a potent activator of the TLR4 pathway[10]. SAA3 can induce IL22 expression in bone marrowderived neutrophils[7] and in in vitro-differentiated Th17 cells[11]

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