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Oral intake of protein leads to tolerance through the induction of regulatory T cells (Tr cells) in mesenteric lymph nodes (MLNs). Here we show that the inhibition of cyclooxygenase-2 (COX-2) in vivo suppressed oral tolerance and was associated with enhanced differentiation of interleukin (IL)-4-producing T cells and reduced Foxp3+ Tr-cell differentiation in MLN. As a result, the functional suppressive capacity of these differentiated mucosal T cells was lost. IL-4 was causally related to loss of tolerance as treatment of mice with anti-IL-4 antibodies during COX-2 inhibition restored tolerance. Dendritic cells (DCs) in the MLN differentially expressed COX-2 and reductionist experiments revealed that selective inhibition of the enzyme in these cells inhibited Foxp3+ Tr-cell differentiation in vitro. Importantly, the inhibition of COX-2 in MLN-DC caused increased GATA-3 expression and enhanced IL-4 release by T cells, which was directly related to impaired Tr-cell differentiation. These data provide crucial insights into the mechanisms driving de novo Tr-cell induction and tolerance in the intestine.
Here we show that the inhibition of COX-2 during protein feed caused loss of tolerance induction, which was associated with an enhanced T-cell-derived IL-4 production and defective Tr-cell differentiation in the MLN. Crucially, treatment of mice with anti-IL-4 antibodies before COX-2 inhibition and protein feed restored oral tolerance. As, predominantly, DC in the MLN expressed COX-2, the role of the enzyme in mucosal T-cell differentiation was further investigated in vitro. COX-2 expression in MLN-DC stimulated the TGF-β- and retinoic acid-dependent conversion of naive T cells into Foxp3+ Tr cells. Reciprocally, the inhibition of COX-2 in MLN-DC increased GATA-3 expression and IL-4 secretion by the differentiating T cells. The differentiation of the IL-4-producing cells in the absence of functional COX-2 was directly related to loss of mucosal tolerance as exogenous IL-4 blocked MLN-DC-driven differentiation of Foxp3+ mucosal Tr cells. These data establish that COX-2 in MLN-DC is required to control the GATA-3/IL-4 axis, allowing the differentiation of mucosal Tr cells and subsequent tolerance.
In this study, we show that COX-2 expression in MLN-DC is involved in the induction of Tr cells during oral tolerance. COX-2 acts by downregulating GATA-3 and IL-4 release in differentiating T cells. IL-4 was found to be a crucial factor that inhibits oral tolerance and impedes the conversion of naive T cells into mucosal Tr cells during COX-2 inhibition. Our data shed new light on the earlier findings showing a role of COX-2 in mucosal homeostasis,19, 20, 21 as they show that COX-2-dependent arachidonic acid metabolites determine the phenotype of the adaptive intestinal immune responses and regulate de novo Tr-cell induction in the mucosal immune system by the suppression of IL-4-producing T cells.
Our data, generated in mouse models, show a crucial role for COX-2-dependent arachidonic acid metabolites in the induction of adaptive regulatory T cells and maintenance of mucosal tolerance in the intestine. Whether this exact mechanism of regulation also applies to the human situation will require extensive further research. Clearly, many reports support the notion that prostaglandin-mediated regulation also occurs in the human intestine. In the past decades, the administration of inhibitors of COX enzymes, denoted as non-steroidal anti-inflammatory drugs, to patients with chronic inflammatory intestinal disease has become more controversial due to the effects of exacerbation of the disease.46, 47, 48, 49 Moreover, recently, a major new Crohn's disease susceptibility locus was identified close to the gene PTGER4 encoding EP4,50 further supporting the idea that modulating inflammation through long-term intake of COX-2 inhibitors may interfere with crucial immune regulatory processes and may therefore encompass threats to intestinal homeostasis.
We carried out large-scale transcriptomic and metabolomic analyses to decipher the short-term acclimation of the brown algal model E. siliculosus to Cu stress, and compared these data to results known for other abiotic stressors. This comparison demonstrates that Cu induces oxidative stress in E. siliculosus as illustrated by the transcriptomic overlap between Cu and H2O2 treatments. The common response to Cu and H2O2 consisted in the activation of the oxylipin and the repression of inositol signaling pathways, together with the regulation of genes coding for several transcription-associated proteins. Concomitantly, Cu stress specifically activated a set of genes coding for orthologs of ABC transporters, a P1B-type ATPase, ROS detoxification systems such as a vanadium-dependent bromoperoxidase, and induced an increase of free fatty acid contents. Finally we observed, as a common abiotic stress mechanism, the activation of autophagic processes on one hand and the repression of genes involved in nitrogen assimilation on the other hand.
Copper is extremely toxic at high concentrations, and induces oxidative stress by altering electron transfer reactions such as photosynthesis and respiration. In our study, we observed a range of different acclimation processes on the molecular level (transcriptomic and metabolite profiling) before the alga exhibited a decrease in photosynthetic yield. Such a decrease in photosynthetic yield results in the alteration of several physiological processes in E. siliculosus, such as the formation of heavy metal-substituted chlorophylls [14], reduced carbon fixation and depletion of reducing equivalents. Effectively, since nitrate reduction directly relies on NADH and FADH2 produced by photosynthesis [35], any condition altering photosynthesis (e.g. abiotic stress) may directly affect the regulation of N assimilation and the associated primary amino acid metabolism [36] or vice versa. We observed that Cu-stressed E. siliculosus down-regulated genes coding for enzymes related to N assimilation. This down-regulation was not related to a decrease of the pool of free primary amino acids. Moreover, an increase in the content of aromatic amino acids was recorded together with an induction of genes encoding proteins involved in the autophagy process, in particular those related to ubiquitination such as putative E3 ubiquitin ligases, and proteins involved in the proteasome complexes. These observations are similar to previous results published in E. siliculosus on response to other stress conditions [25], and suggest that alteration of N assimilation and carbon fixation is compensated by degradation of damaged proteins and recycling of amino acids. Similar processes have been identified in land plants during stress response or in diatoms under nitrogen starvation [37, 38]. Concomitantly to the down-regulation of genes involved in N assimilation under copper stress, we observed an increase of free fatty acids. Similar links between amino- and fatty acid metabolism have previously been observed in other algae, such as Chlamydomonas reinhardtii[39]. Altogether, these data suggest that a substantial part of the response of E. siliculosus to short term copper stress consists in balancing primary metabolic processes. Although we can currently only speculate about the exact physiological benefits of each of the observed adjustments, two important functions may be (1) the compensation for stress-induced changes in photosynthesis and (2) the reduction of the energetic budget for nitrogen assimilation. These changes in primary metabolic processes are undoubtedly tightly tied to the specific stress responses and signaling mechanisms discussed below.
By combining the data obtained in both positive and negative ion mode by UPLC-MS and by GC-MS, 47 metabolites corresponding to fatty acids, oxylipins, and amino acids could be reliably identified. Multivariate statistical analyses of metabolite data were carried out using SIMCA-P (12.0.1, Umetrics, Umeå, Sweden). Data were log10-transformed and normalized using Pareto scaling. Partial least squares discriminant analysis (PLS-DA) was carried out on the 392 monoisotopic peaks detected by the UPLC-MS analysis, and also independently on free fatty acids and on the amino acids. Hierarchical clustering analysis of the 392 peaks was carried out with TigrMeV as described for gene expression data, except that metabolite quantities were normalized by dividing all values by the highest value obtained in any of the conditions tested (all normalized values ranged from 0 to 1) instead of calculating log2-ratios. A similar analysis was also performed for the 47 identified metabolites, and their relative quantities were further analysed using a two-way ANOVA in analogy to the gene expression data (see above).
For many rare or endangered anurans, monitoring is achieved via auditory cues alone. Human-performed audio surveys are inherently biased, and may fail to detect animals when they are present. Automated audio recognition tools offer an alternative mode of observer-free monitoring. Few commercially available platforms for developing these tools exist, and little research has investigated whether these tools are effective at detecting rare vocalization events. We generated a recognizer for detecting the vocalization of the endangered Houston toad Anaxyrus houstonensis using SongScope bioacoustics software. We developed our recognizer using a large sample of training data that included only the highest quality of recorded audio (i.e., low noise, no interfering vocalizations) divided into small, manageable batches. To track recognizer performance, we generated an independent set of test data through randomly sampling a large population of audio known to possess Houston toad vocalizations. We analyzed training data and test data recursively, using a criterion of zero tolerance for false-negative detections. For each step, we incorporated a new batch of training data into the recognizer. Once we included all training data, we manually verified recognizer performance against one full month (March 2014) of audio taken from a known breeding locality. The recognizer successfully identified 100% of all training data and 97.2% of all test data. However, there is a trade-off between reducing false-negative and increasing false-positive detections, which limited the usefulness of some features of SongScope. Methods of automated detection represent a means by which we may test the efficacy of the manual monitoring techniques currently in use. The ability to search any collection of audio recordings for Houston toad vocalizations has the potential to challenge the paradigms presently placed on monitoring for this species of conservation concern. 153554b96e
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