Translocated LPS Might Cause Endotoxin Tolerance in Circulating Monocytes of Cystic Fibrosis Patients

Cystic Fibrosis (CF) is an inherited pleiotropic disease that results from abnormalities in the gene codes of a chloride channel. The lungs of CF patients are chronically infected by several pathogens but bacteraemia have rarely been reported in this pathology. Besides that, circulating monocytes in CF patients exhibit a patent Endotoxin Tolerance (ET) state since they show a significant reduction of the inflammatory response to bacterial stimulus. Despite a previous description of this phenomenon, the direct cause of ET in CF patients remains unknown. In this study we have researched the possible role of microbial/endotoxin translocation from a localized infection to the bloodstream as a potential cause of ET induction in CF patients. Plasma analysis of fourteen CF patients revealed high levels of LPS compared to healthy volunteers and patients who suffer from Chronic Obstructive Pulmonary Disease. Experiments in vitro showed that endotoxin concentrations found in plasma of CF patients were enough to induce an ET phenotype in monocytes from healthy controls. In agreement with clinical data, we failed to detect bacterial DNA in CF plasma. Our results suggest that soluble endotoxin present in bloodstream of CF patients causes endotoxin tolerance in their circulating monocytes

A multi-site collaborative study of the hostile priming effect

Data Accessibility Statement: See Table 1.Supplementary data: Peer Review History - docx file - available online at: https://online.ucpress.edu/collabra/article/7/1/18738/116070/A-Multi-Site-Collaborative-Study-of-the-Hostile#supplementary-data .In a now-classic study by Srull and Wyer (1979), people who were exposed to phrases with hostile content subsequently judged a man as being more hostile. And this “hostile priming effect” has had a significant influence on the field of social cognition over the subsequent decades. However, a recent multi-lab collaborative study (McCarthy et al., 2018) that closely followed the methods described by Srull and Wyer (1979) found a hostile priming effect that was nearly zero, which casts doubt on whether these methods reliably produce an effect. To address some limitations with McCarthy et al. (2018), the current multi-site collaborative study included data collected from 29 labs. Each lab conducted a close replication (total N = 2,123) and a conceptual replication (total N = 2,579) of Srull and Wyer’s methods. The hostile priming effect for both the close replication (d = 0.09, 95% CI [-0.04, 0.22], z = 1.34, p = .16) and the conceptual replication (d = 0.05, 95% CI [-0.04, 0.15], z = 1.15, p = .58) were not significantly different from zero and, if the true effects are non-zero, were smaller than what most labs could feasibly and routinely detect. Despite our best efforts to produce favorable conditions for the effect to emerge, we did not detect a hostile priming effect. We suggest that researchers should not invest more resources into trying to detect a hostile priming effect using methods like those described in Srull and Wyer (1979).We have no funding to declare for this project

Position-dependent expression of GADD45 alpha in rat brain tumours

Although the complex and multifactorial process of tumour growth has been extensively studied for decades, our understanding of the fundamental relationship between tumour growth dynamics and genetic expression profile remains incomplete. Recent studies of tumour dynamics indicate that gene expression in solid tumours would depend on the distance from the centre of the tumour. Since tumour proliferative activity is mainly localised to its external zone, and taking into account that generation and expansion of genetic mutations depend on the number of cell divisions, important differences in gene expression between central and peripheral sections of the same tumour are to be expected. Here, we have studied variations in the genetic expression profile between peripheral and internal samples of the same brain tumour. We have carried out microarray analysis of mRNA expression, and found a differential profile of genetic expression between the two cell subsets. In particular, one major nuclear protein that regulates cell responses to DNA-damaging and stress signals, GADD45 alpha, was expressed at much lower levels in the peripheral zone, as compared to tumour core samples. These differences in GADD45 alpha mRNA transcription levels have been confirmed by quantitative analysis via real time PCR, and protein levels of GADD45 alpha also exhibit the same pattern of differential expression. Our findings suggest that GADD45 alpha might play a major role in the regulation of brain tumour invasive potential

A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis

T helper 9 (Th9) cells contribute to lung inflammation and allergy as sources of interleukin-9 (IL-9). However, the mechanisms by which IL-9/Th9 mediate immunopathology in the lung are unknown. Here we report an IL-9-driven positive feedback loop that reinforces allergic inflammation. We show that IL-9 increases IL-2 production by mast cells, which leads to expansion of CD25 + type 2 innate lymphoid cells (ILC2) and subsequent activation of Th9 cells. Blocking IL-9 or inhibiting CD117 (c-Kit) signalling counteracts the pathogenic effect of the described IL-9-mast cell-IL-2 signalling axis. Overproduction of IL-9 is observed in expectorates from cystic fibrosis (CF) patients, and a sex-specific variant of IL-9 is predictive of allergic reactions in female patients. Our results suggest that blocking IL-9 may be a therapeutic strategy to ameliorate inflammation associated with microbial colonization in the lung, and offers a plausible explanation for gender differences in clinical outcomes of patients with CF