Transcription factor c-Rel mediates communication between commensal bacteria and mucosal lymphocytes.

The NF-κB transcription factor c-Rel plays a crucial role in promoting and regulating immune responses and inflammation. However, the function of c-Rel in modulating the mucosal immune system is poorly understood. T follicular helper (Tfh) cells and IgA production in gut-associated lymphoid tissues (GALT) such as Peyer's patches (PPs) are important for maintaining the intestinal homeostasis. Here, c-Rel was identified as an essential factor regulating intestinal IgA generation and function of Tfh cells. Genetic deletion of c-Rel resulted in the aberrant formation of germinal centers (GCs) in PPs, significantly reduced IgA generation and defective Tfh cell differentiation. Supporting these findings, the Ag-specific IgA response to Citrobacter rodentium was strongly impaired in c-Rel-deficient mice. Interestingly, an excessive expansion of segmented filamentous bacteria (SFB) was observed in the small intestine of animals lacking c-Rel. Yet, the production of IL-17A, IgA, and IL-21, which are induced by SFB, was impaired due to the lack of transcriptional control by c-Rel. Collectively, the transcriptional activity of c-Rel regulates Tfh cell function and IgA production in the gut, thus preserving the intestinal homeostasis.

The NF-κB transcription factor c-Rel controls host defense against Citrobacter rodentium.

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.

Intestinal development and homeostasis require activation and apoptosis of diet-reactive T cells.

The impact of food antigens on intestinal homeostasis and immune function is poorly understood. Here, we explored the impact of dietary antigens on the phenotype and fate of intestinal T cells. Physiological uptake of dietary proteins generated a highly activated CD44+Helios+CD4+ T cell population predominantly in Peyer patches. These cells are distinct from regulatory T cells and develop independently of the microbiota. Alimentation with a protein-free, elemental diet led to an atrophic small intestine with low numbers of activated T cells, including Tfh cells and decreased amounts of intestinal IgA and IL-10. Food-activated CD44+Helios+CD4+ T cells in the Peyer patches are controlled by the immune checkpoint molecule PD-1. Blocking the PD-1 pathway rescued these T cells from apoptosis and triggered proinflammatory cytokine production, which in IL-10-deficient mice was associated with intestinal inflammation. In support of these findings, our study of patients with Crohn's disease revealed significantly reduced frequencies of apoptotic CD4+ T cells in Peyer patches as compared with healthy controls. These results suggest that apoptosis of diet-activated T cells is a hallmark of the healthy intestine.

Do consumers care about substances of very high concern in articles?

BACKGROUND: Consumers have the right to inquire whether a consumer article contains substances of very high concern ('SVHC right to know'). This communication tool is designed to stimulate suppliers to substitute such ingredients. A survey among 1321 consumers with high motivation and interest in harmful substances in everyday products was conducted to understand the acceptance of this 'right to know' among consumers. RESULTS: Only one out of seven survey participants stated to be well informed about the 'SVHC right to know' with nearly all of them having good self-reported chemical knowledge. Three quarters of the participants who are not working with chemicals or REACH at their workplace have never heard about the 'SVHC right to know'. Every second participant declared their interest to search for more information about an SVHC in a certain article, but, in fact, not more than 4% of all participants inquired for SVHCs with various methods. Only 1% would buy an SVHC-containing article with no strings attached. While detailed comments by some survey participants showed a high level of understanding of the issue, many respondents were not sure what the SVHC information means for their daily life. They declared that they would inform themselves, reduce the use of the article with SVHCs, circulate this information, or throw such an article into the garbage. Most study participants suggested improvements of the 'SVHC right to know'. The preferred suggestions were a ban of SVHCs, easily understandable information on the packaging, full ingredient declaration on the articles, or no need to inquire for every single item, while smartphone applications for SVHC requests were the least popular suggestion in all age groups. CONCLUSIONS: Various reasons could be identified why most consumers-even these motivated and interested ones-do not use the 'SVHC right to know'. This allowed developing recommendations for improving the effectiveness of this communication instrument on the way to the gradual elimination of SVHCs in consumer articles.

Interested consumers' awareness of harmful chemicals in everyday products.

BACKGROUND: Everyday products can contain a multitude of harmful substances unnoticed by most consumers, because established risk communication channels reach only part of the society. The question is, whether at least interested and informed consumers are able to use risk communication tools and assess harmful chemicals in products. RESULTS: An online survey investigated the awareness of 1030 consumers on harmful substances in everyday items. Participating consumers' education level, knowledge in chemistry, and motivation were above society's average. Although a large number of responses showed that survey participants were familiar with several aspects of the issue, the results revealed that knowledge in chemistry helped, but was not enough. Many participants assumed that products with an eco-label, natural personal care products, products without hazard pictograms or products produced in the European Union would not contain harmful substances. Most participants indicated to use hazard pictograms, information on the packaging, reports in the media, and environmental and consumer organizations as information sources, while information by authorities and manufacturers were not named frequently and did not receive high confidence. Smartphone applications were not indicated by many participants as information sources. The information sources most trusted were environmental and consumer organizations, hazard pictograms, and lists of ingredients on the containers. The declared confidence in certain risk communication instruments did not always correspond to the use frequencies indicated. Nearly all participants considered legislators as responsible for the reduction of harmful substances in consumer products. CONCLUSIONS: Misconceptions about harmful substances in products can be dangerous for the personal health and the environment. The survey indicates that motivation, educational level, and chemical expertise do not automatically provide an appropriate understanding of harmful substances in products. If well-informed consumers are not sufficiently capable to use risk information elements as revealed in this study, then this will be even more the case for the general public. Consumer awareness should be stipulated by an improved information strategy about chemical risks in consumer products with an extensive participation of the target groups and by more efforts by authorities and manufactures to build trust and to provide easily understandable information.

Prevention of colitis-associated cancer by selective targeting of immunoproteasome subunit LMP7.

Chronic inflammation is a well-known risk factor in development of intestinal tumorigenesis, although the exact mechanisms underlying development of colitis-associated cancer (CAC) still remain obscure. The activity and function of immunoproteasome has been extensively analyzed in the context of inflammation and infectious diseases. Here, we show that the proteasomal immunosubunit LMP7 plays an essential role in development of CAC. Mice devoid of LMP7 were resistant to chronic inflammation and formation of neoplasia, and developed virtually no tumors after AOM/DSS treatment. Our data reveal that LMP7 deficiency resulted in reduced expression of pro-tumorigenic chemokines CXCL1, CXCL2 and CXCL3 as well as adhesion molecule VCAM-1. As a consequence, an impaired recruitment and activity of tumor-infiltrating leukocytes resulting in decreased secretion of cytokines IL-6 and TNF-α was observed. Further, the deletion or pharmacological inhibition of LMP7 and consequent blockade of NF-κB abrogated the production of IL-17A, which possesses a strong carcinogenic activity in the gut. Moreover, in vivo administration of the selective LMP7 inhibitor ONX-0914 led to a marked reduction of tumor numbers in wild-type (WT) mice. Collectively, we identified the immunoproteasome as a crucial mediator of inflammation-driven neoplasia highlighting a novel potential therapeutic approach to limit colonic tumorigenesis.