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• W2989104910 abstract "Mice lacking CD4+ T cells or B cells are highly susceptible to Citrobacter rodentium infection. In this study, we show that the activity of the transcription factor c-Rel in lymphocytes is crucial for clearance of C. rodentium. Mice deficient for c-Rel fail to generate protective antibodies and to eradicate the pathogen. The family of NF-κB transcription factors comprises five closely related subunits that are involved in multiple aspects of adaptive and innate immune responses. Bacterial infections and chronic inflammation activate predominantly the canonical NF-κB pathway consisting of RelA/p50 and c-Rel/p50 dimers 1. The activation of NF-κB leads to rapid proteasomal degradation of IκBα, a main inhibitory protein involved in the regulation of the canonical NF-κB pathway, resulting in translocation of RelA- and c-Rel-containing dimers into the nucleus and induction of target gene expression 2. The potential role of NF-κB in the protective immune responses against C. rodentium has not been investigated in the detail. The functional analysis of mice deficient for the p50 subunit of NF-κB, which can differentially regulate immune responses by building either homodimers or heterodimers with various NF-κB proteins, revealed that this protein is crucial for the eradication of C. rodentium infection 3. Further, mice lacking the atypical IκB protein IκBNS showed impaired Th17 cell responses upon infection with C. rodentium 4. The important role of c-Rel in regulating the function of immune cells prompted us to investigate if this transcription factor is crucial for orchestrating protective immune defense against C. rodentium. To examine the consequences of c-Rel deficiency for the course of C. rodentium infection, rel−/− and WT mice were orally infected with this pathogen and the bacterial numbers (colony forming units, CFU) were determined in the faeces. While WT mice were capable of eliminating the infection within approximiately 20 days, rel−/− animals were not able to clear the pathogen. Of note, the vast majority of c-Rel-deficient mice died between days 105 and 120 post infection (Fig. 1A and B). At day 120 of infection, histological data demonstrated significant crypt hyperplasia and chronic infiltration of inflammatory cells into the colonic lamina propria of mice lacking c-Rel, while the WT intestine did not exhibit any immunopathology due to the clearance of infection within first three weeks (Fig. 1C). When we tested for the localization of C. rodentium on day 90 post infection, we found that, in contrast to the non-detectable levels of the pathogen in WT mice, this bacterium was detected in all examined extra-intestinal organs of rel−/− animals such as pancreas, liver, kidney, and spleen, indicating for translocation and systemic spreading of C. rodentium (Fig. 1D). The high bacterial load outside of the intestine illustrates that c-Rel is an essential factor, which restricts the infection to the intestinal tissue. Innate immune cells such as DCs, macrophages, neutrophils, and innate lymphoid cells play a central role in the early phase of inflammatory responses during infection with C. rodentium. Notably, Rag1−/- rel−/- mice infected with C. rodentium displayed a prolonged survival as compared to Rag1-deficient animals (Supporting Information Fig. 1A), suggesting that innate immune responses may compensate for partially defective function of intestinal DCs and innate lymphoid cells in mice lacking c-Rel that was previously described 5. T and B lymphocytes play an essential role during the elimination of C. rodentium. Rag1−/− mice lacking mature T and B cells are not able to eradicate this pathogen 6. The NF-κB signaling pathway is known to regulate the activity of lymphocytes, however the contribution of individual NF-κB subunits to protective immune responses against pathogenic bacteria is only partially understood. To define the key effector mechanism involved in the c-Rel-mediated defense against C. rodentium infection, we next examined CD4+ T cells isolated from the colonic lamina propria at day 12 post infection. We found that the frequency of IL-17A+CD4+ and IFN-γ+CD4+ T cells was significantly increased in the colon of WT mice as compared to rel−/− animals during the course of infection. Particularly, the double-positive IL-17A+IFN-γ+CD4+ T cell population, which is required for the clearance of C. rodentium, was significantly diminished in mice lacking the transcription factor c-Rel, suggesting that a defective T-cell response contributes to the observed phenotype (Fig. 2A–D). It is known that mice lacking c-Rel have a substantially impaired IL-2 production and that low secretion of IL-12 and IL-23 may also contribute to defective expression of cytokines by T cells during infection with C. rodentium 7, 8. When we supplied IL-2 exogenously into rel−/− T cell cultures, we observed similar proliferation and IFN-γ production in Th1 cells compared to WT controls (Supporting Information Fig. 1B and C). Of note, the nuclear translocation of RelA, a transcription factor related to c-Rel, was comparable between WT and rel−/- CD4+ T lymphocytes following T cell activation, suggesting for an intact RelA signaling in the absence of c-Rel (Supporting Information Fig. 1D). Our previous data revealed that the atypical IκB protein IκBNS was able to interact with c-Rel in the nucleus of T cells 9. Since IκBNS does not contain a DNA-binding motif, this protein may require interaction with c-Rel to bind to target DNA sequences. Interestingly, both proteins, c-Rel and IκBNS appear to be required for the clearance of C. rodentium. It was previously shown that mice lacking c-Rel were resistant to collagen-induced arthritis and were not able to elicit a specific IgG antibody response to collagen type II (CII) 10. Because c-Rel plays an important role for antibody generation, we next investigated C. rodentium-specific antibody production at day 12 post infection in serum and colon cultures. During infection with C. rodentium, rel−/− mice had only marginal C. rodentium-specific IgG antibody levels in serum and colon as compared to high amount of bacteria-specific antibodies in WT animals (Fig 2E and F). Since clearance of C. rodentium infection is crucially dependent on humoral immune responses to bacterial proteins, we conclude that c-Rel-mediated generation of C. rodentium-specific antibodies is the key step in prevention of systemic spreading and elimination of this bacterium. Thus, c-Rel is required for protective antibacterial responses and for limitation of C. rodentium colonization to intestinal tissues. This study was supported by the Von Behring-Röntgen-Stiftung (Ulrich Steinhoff und Maik Luu), Manchot Stiftung (Rossana Romero), Loewe center novel drug targets against poverty related neglected tropical infectious disease (DRUID, Ulrich Steinhoff und Rouzbeh Mahdavi), Studienstiftung des deutschen Volkes (Maik Luu), and FAZIT-Stiftung (Hanna Leister and Alexander Visekruna). Open access funding enabled and organized by Projekt DEAL. The authors declare no commercial or financial conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W2989104910 date "2019-11-25" @default.
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• W2989104910 title "The NF‐κB transcription factor c‐Rel controls host defense against Citrobacter rodentium" @default.
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• W2989104910 doi "https://doi.org/10.1002/eji.201948314" @default.
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