Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is characterized by proliferation of malignant T cells in a chronic inflammatory environment. With disease progression, bacteria colonize the compromised skin barrier and half of CTCL patients die of infection rather than from direct organ involvement by the malignancy. Clinical data indicate that bacteria play a direct role in disease progression, but little is known about the mechanisms involved. Here, we demonstrate that bacterial isolates containing staphylococcal enterotoxin A (SEA) from the affected skin of CTCL patients, as well as recombinant SEA, stimulate activation of signal transducer and activator of transcription 3 (STAT3) and upregulation of interleukin (IL)-17 in immortalized and primary patient-derived malignant and nonmalignant T cells. Importantly, SEA induces STAT3 activation and IL-17 expression in malignant T cells when cocultured with nonmalignant T cells, indicating an indirect mode of action. In accordance, malignant T cells expressing an SEA-nonresponsive T-cell receptor variable region β chain are nonresponsive to SEA in monoculture but display strong STAT3 activation and IL-17 expression in cocultures with SEA-responsive nonmalignant T cells. The response is induced via IL-2 receptor common γ chain cytokines and a Janus kinase 3 (JAK3)-dependent pathway in malignant T cells, and blocked by tofacitinib, a clinical-grade JAK3 inhibitor. In conclusion, we demonstrate that SEA induces cell cross talk-dependent activation of STAT3 and expression of IL-17 in malignant T cells, suggesting a mechanism whereby SEA-producing bacteria promote activation of an established oncogenic pathway previously implicated in carcinogenesis

TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain

Background: The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that immune mediators, such as cytokines, can have a significant effect on brain function and behaviour. More rarely have studies used disease models that are representative of human disorders. Methods: Here we use a well-characterised animal model of psoriasis-like skin inflammation—imiquimod—to investigate the effects of tissue-specific peripheral inflammation on the brain. We used full genome array, flow cytometry analysis of immune cell infiltration, doublecortin staining for neural precursor cells and a behavioural read-out exploiting natural burrowing behaviour. Results: We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5). Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity. Conclusions: These findings demonstrate that cutaneous, peripheral immune stimulation is associated with significant leukocyte infiltration into the brain and suggest that chemokines may be amongst the key mediators driving this response

GATA3 Expression Is Decreased in Psoriasis and during Epidermal Regeneration; Induction by Narrow-Band UVB and IL-4

Psoriasis is characterized by hyperproliferation of keratinocytes and by infiltration of activated Th1 and Th17 cells in the (epi)dermis. By expression microarray, we previously found the GATA3 transcription factor significantly downregulated in lesional psoriatic skin. Since GATA3 serves as a key switch in both epidermal and T helper cell differentiation, we investigated its function in psoriasis. Because psoriatic skin inflammation shares many characteristics of epidermal regeneration during wound healing, we also studied GATA3 expression under such conditions

Metabolic changes of salicylic acid-elicited Catharanthus roseus cell suspension cultures monitored by NMR-based metabolomics

The effect of salicylic acid (SA) on the metabolic profile of Catharanthus roseus suspension cells throughout a time course (0, 6, 12, 24, 48 and 72 h after treatment) was investigated using NMR spectroscopy and multivariate data analysis. When compared to control cell lines, SA-treated cells showed a high level of sugars (glucose and sucrose) up to 48 h after treatment, followed by a dynamic change in amino acids, phenylpropanoids, and tryptamine. Additionally, one compound—2,5-dihydroxybenzoic-5-O-glucoside—was detected solely in SA-treated cells

Zinc finger proteins act as transcriptional repressors of alkaloid biosynthesis genes in Catharanthus roseus

Plant science

Spread of psoriasiform inflammation to remote tissues is restricted by the atypical chemokine receptor ACKR2

Elucidating the poorly defined mechanisms by which inflammatory lesions are spatially restricted in vivo, is of critical importance in understanding skin disease. Chemokines are the principal regulators of leukocyte migration and are essential in the initiation and maintenance of inflammation. The membrane-bound psoriasis associated atypical chemokine receptor ACKR2 binds, internalises and degrades most pro-inflammatory CC-chemokines. Here we investigate the role of ACKR2 in limiting the spread of cutaneous psoriasiform inflammation to sites that are remote from the primary lesion.  Circulating factors capable of regulating ACKR2 function at remote sites were identified and examined using a combination of clinical samples, relevant primary human cell cultures, in vitro migration assays and the imiquimod-induced model of psoriasiform skin inflammation. Localised inflammation and IFN together upregulate ACKR2 in remote tissues, protecting them from the spread of inflammation. ACKR2 controls inflammatory T-cell chemotaxis and positioning within the skin, preventing an epidermal influx that is associated with lesion development. Our results have important implications for our understanding of how spatial restriction is imposed on the spread of inflammatory lesions, and highlight systemic ACKR2 induction as a therapeutic strategy in the treatment and prevention of psoriasis and potentially a broad range of other immune-mediated diseases

Circulating MicroRNAs Are Not Eliminated by Hemodialysis

BACKGROUND: Circulating microRNAs are stably detectable in serum/plasma and other body fluids. In patients with acute kidney injury on dialysis therapy changes of miRNA patterns had been detected. It remains unclear if and how the dialysis procedure itself affects circulating microRNA level. METHODS: We quantified miR-21 and miR-210 by quantitative RT-PCR in plasma of patients with acute kidney injury requiring dialysis and measured pre- and post-dialyser miRNA levels as well as their amount in the collected spent dialysate. Single treatments using the following filters were studied: F60 S (1.3 m(2), Molecular Weight Cut Off (MWCO): 30 kDa, n = 8), AV 1000 S (1.8 m(2), MWCO: 30 kDa, n = 6) and EMiC 2 (1.8 m(2), MWCO: 40 kDa, n = 6). RESULTS: Circulating levels of miR-21 or -210 do not differ between pre- and post-dialyzer blood samples independently of the used filter surface and pore size: miR-21: F60S: p = 0.35, AV 1000 S p = 1.0, EMiC2 p = 1.0; miR-210: F60S: p = 0.91, AV 1000 S p = 0.09, EMiC2 p = 0.31. Correspondingly, only traces of both miRNAs could be found in the collected spent dialysate and ultrafiltrate. CONCLUSIONS: In patients with acute kidney injury circulating microRNAs are not removed by dialysis. As only traces of miR-21 and -210 are detected in dialysate and ultrafiltrate, microRNAs in the circulation are likely to be transported by larger structures such as proteins and/or microvesicles. As miRNAs are not affected by dialysis they might be more robust biomarkers of acute kidney injury

Embodiment and the origin of interval timing: kinematic and electromyographic data

Recent evidence suggests that interval timing (the judgment of durations lasting from approximately 500 ms. to a few minutes) is closely coupled to the action control system. We used surface electromyography (EMG) and motion capture technology to explore the emergence of this coupling in 4-, 6-, and 8-month-olds. We engaged infants in an active and socially relevant arm-raising task with 7 cycles and response period. In one condition cycles were slow (every 4 seconds) in another they were fast (every 2 seconds). In the slow condition, we found evidence of time locked sub-threshold EMG activity even in the absence of any observed overt motor responses at all 3 ages. This study shows that EMGs can be a more sensitive measure of interval timing in early development than overt behavior

Two GCC boxes and AP2/ERF-domain transcription factor ORA59 in jasmonate/ethylene-mediated activation of the PDF1.2 promoter in Arabidopsis

Plant defense against microbial pathogens depends on the action of several endogenously produced hormones, including jasmonic acid (JA) and ethylene (ET). In defense against necrotrophic pathogens, the JA and ET signaling pathways synergize to activate a specific set of defense genes including PLANT DEFENSIN1.2 (PDF1.2). The APETALA2/Ethylene Response Factor (AP2/ERF)-domain transcription factor ORA59 acts as the integrator of the JA and ET signaling pathways and is the key regulator of JA- and ET-responsive PDF1.2 expression. The present study was aimed at the identification of elements in the PDF1.2 promoter conferring the synergistic response to JA/ET and interacting with ORA59. We show that the PDF1.2 promoter was activated synergistically by JA and the ET-releasing agent ethephon due to the activity of two GCC boxes. ORA59 bound in vitro to these GCC boxes and trans-activated the PDF1.2 promoter in transient assays via these two boxes. Using the chromatin immunoprecipitation technique we were able to show that ORA59 bound the PDF1.2 promoter in vivo. Finally, we show that a tetramer of a single GCC box conferred JA/ethephon-responsive expression, demonstrating that the JA and ET signaling pathways converge to a single type of GCC box. Therefore ORA59 and two functionally equivalent GCC box binding sites form the module that enables the PDF1.2 gene to respond synergistically to simultaneous activation of the JA and ET signaling pathways

The relationship between a child's postural stability and manual dexterity

The neural systems responsible for postural control are separate from the neural substrates that underpin control of the hand. Nonetheless, postural control and eye-hand coordination are linked functionally. For example, a stable platform is required for precise manual control tasks (e.g. handwriting) and thus such skills often cannot develop until the child is able to sit or stand upright. This raises the question of the strength of the empirical relationship between measures of postural stability and manual motor control. We recorded objective computerised measures of postural stability in stance and manual control in sitting in a sample of school children (n = 278) aged 3–11 years in order to explore the extent to which measures of manual skill could be predicted by measures of postural stability. A strong correlation was found across the whole sample between separate measures of postural stability and manual control taken on different days. Following correction for age, a significant but modest correlation was found. Regression analysis with age correction revealed that postural stability accounted for between 1 and 10 % of the variance in manual performance, dependent on the specific manual task. These data reflect an interdependent functional relationship between manual control and postural stability development. Nevertheless, the relatively small proportion of the explained variance is consistent with the anatomically distinct neural architecture that exists for ‘gross’ and ‘fine’ motor control. These data justify the approach of motor batteries that provide separate assessments of postural stability and manual dexterity and have implications for therapeutic intervention in developmental disorders