Abstract
Escherichia coli and Klebsiella pneumoniae are opportunistic pathogens that are commonly associated with infections at mucosal surfaces, such as the lung or the gut. The host response against these types of infections includes the release of epithelial-derived antimicrobial factors such as lipocalin-2 (LCN-2), a protein that specifically inhibits the iron acquisition of Enterobacteriaceae by binding and neutralizing the bacterial iron-scavenging molecule enterobactin. Regulation of epithelial antimicrobial responses, including the release of LCN-2, has previously been shown to depend on IL-22, a cytokine produced by innate lymphoid cells type 3 (ILC3) during Enterobacteriaceae infections. However, much remains unknown about the extent to which antimicrobial responses are regulated by IL-22 and how IL-22 regulates the expression and production of LCN-2 in intestinal epithelial cells (IECs). Our study demonstrates how IL-22-induced activation of STAT3 synergizes with NF-κB-activating cytokines to enhance LCN-2 expression in human IECs and elucidates how ILC3 are involved in LCN-2-mediated host defense against Enterobacteriaceae. Together, these results provide new insight into the role of ILC3 in regulating LCN-2 expression in human IECs and could prove useful in future studies aimed at understanding the host response against Enterobacteriaceae as well as for the development of antimicrobial therapies against Enterobacteriaceae-related infections.
Highlights
Escherichia coli and Klebsiella pneumoniae are opportunistic pathogens that are commonly associated with infections at mucosal surfaces, such as the lung or the gut
To better understand the role of IL-22 in the regulation of antimicrobial responses in human intestinal epithelial cells (IECs), we aimed to identify how IL-22 affects antimicrobial gene expression in the context of other cytokines commonly expressed during Enterobacteriaceae infection, namely IL-17A, TNF, and IFN-␥ (17, 24, 46 – 49)
Our results demonstrate that LCN2, DEFB4, NOS2, and S100A9 are consistently up-regulated on a transcriptional level in both human IEC cell lines and primary human IECs upon stimulation with IL22, IL-17A, TNF, and IFN-␥ and that hBD-2, LCN-2, and Nitric oxide (NO) concentrations are elevated in supernatants in response to these cytokines
Summary
Escherichia coli and Klebsiella pneumoniae are opportunistic pathogens that are commonly associated with infections at mucosal surfaces, such as the lung or the gut. Regulation of epithelial antimicrobial responses, including the release of LCN-2, has previously been shown to depend on IL-22, a cytokine produced by innate lymphoid cells type 3 (ILC3) during Enterobacteriaceae infections. Intestinal epithelial cells (IECs) play a crucial role in the protection against such infections by producing a variety of antimicrobial factors [7]. One of the cell types that plays an important role in the regulation of antimicrobial responses in IECs are innate lymphoid cells type 3 (ILC3) [17, 18] These cells are tissue-resident under homeostatic conditions (19 –21) and are marked by the expression of transcription factors Retinoic Acid-Related (RAR)-related orphan receptor-␥ [22] and aryl hydrocarbon receptor [23].
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