Abstract
CCN1 is well studied in terms of its functions in injury repair, cell adhesion survival and apoptosis, bacterial clearance and mediation of inflammation-related pathways, such as the TLR2/4 pathways. However, the role of CCN1 protein and its interaction with TLR2/4 pathways in intestinal epithelial cells was not elucidated after Listeria monocytogenes infection. The results of this study confirm that L. monocytogenes infection induced intestinal inflammation and increased the protein expression of CCN1, TLR2, TLR4 and p38, which followed a similar tendency in the expression of genes related to the TLR2/4 pathways. In addition, organoids infected by L. monocytogenes showed a significant increase in the expression of CCN1 and the activation of TLR2/4 pathways. Furthermore, pre-treatment with CCN1 protein to organoids infected by L. monocytogenes could increase the related genes of TLR2/4 pathways and up-regulate the expression of TNF, and increase the count of pathogens in organoids, which indicates that the interaction between the CCN1 protein and TLR2/4 signaling pathways in intestinal epithelial cells occurred after L. monocytogenes infection. This study will provide a novel insight of the role of CCN1 protein after L. monocytogenes infection in the intestine.
Highlights
Listeria monocytogenes is a short Gram-positive flagellar and ubiquitous intracellular bacterium that causes listeriosis in immunocompromised individuals, with a case fatality rate of up to 30% [1]
The results show that the pre-treatment of communication network factor 1 (CCN1) protein significantly increased the mRNA expression levels of TLR2/4-pathway-related genes (TLR2, TLR4, myeloid differentiation factor 88 (MyD88), IRAK1, TAK1 and p38) (Figure 7A–F), which could lead to the increase in the mRNA expression level of TNF after L. monocytogenes infection (Figure 7G)
The results of this study show a significant up-regulated response in TNF and IL-1β expression levels caused by L. monocytogenes infection in mice and organoids, which indicates that L. monocytogenes caused the inflammation of intestinal epithelial cells
Summary
Listeria monocytogenes is a short Gram-positive flagellar and ubiquitous intracellular bacterium that causes listeriosis in immunocompromised individuals, with a case fatality rate of up to 30% [1]. Intestinal epithelial cells, which respond to intruders and their cellular molecules by displaying an inflammatory state, play a crucial role in the immune response to pathogens [2]. Toll-like receptors (TLRs), expressed in the intestinal epithelial cells, are the phylogenetically conserved mediators of innate immunity that can discriminate intestinal microbiota and respond to pathogenic microbes by recognizing pathogen-associated molecular patterns (PAMPs) [3,4]. TLR4 was commonly reported to act as a signaling receptor of lipopolysaccharide (LPS), a Gram-negative bacterial component, in a recent study, TLR4 of macrophages were activated through cellular communication network factor 1 (CCN1), which could recognize peptidoglycan (PGN) of S. aureus [8]. Upon recognizing PAMPs, TLR2 or TLR4 could lead signaling to produce various inflammatory cytokines through the activation of myeloid differentiation factor 88 (MyD88)-dependent and -independent pathways [9]. The gene expression of regulatory factors of p38 (the MAPKs family) was activated, so as to induce the production of proinflammatory cytokines and chemokines [10]
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