Viral hepatitis is still a public health problem affecting several million people around the world. Neutrophils are polymorphonuclear cells that have a critical role in antibacterial infection. However, the role of neutrophils in viral infection is not fully understood. By using a mouse model of lymphocytic choriomeningitis virus infection-induced viral hepatitis, we observed increased neutrophil recruitment in the liver accompanied by enhanced CD8 T-cell responses. Liver neutrophils expressed high levels of immunomodulatory cytokines, such as C-X-C chemokine ligand 2, arginase-1, inducible nitric oxide synthase and interleukin (IL)-10, demonstrating immunosuppressive properties. Depletion of neutrophils in vivo by a neutralizing antibody resulted in the exacerbation of liver injury and the promotion of T-cell responses at the immune contraction stage. IL-33 significantly induced neutrophil recruitment in the liver and attenuated liver injury by limiting effector T-cell accumulation. Mechanistically, we found that IL-33 promoted the expression of arginase-1 in neutrophils through the type 2 innate lymphoid cell (ILC2)-derived IL-13. Additionally, IL-13 increased the inhibitory effect of neutrophils on CD8 T-cell proliferation in vitro, partially through arginase-1. Finally, we found that IL-13 induced arginase-1 expression, depending on signal transducer and activator of transcription factor 6 (STAT6) signaling. Therefore, IL-33 induced immunosuppressive neutrophils via an ILC2/IL-13/STAT6 axis. Collectively, our findings shed new light on the mechanisms associated with IL-33-triggered neutrophils in the liver and suggest potential targets for therapeutic investigation in viral hepatitis.Cellular and Molecular Immunology advance online publication, 5 February 2018; doi:10.1038/cmi.2017.147.
Interleukin-22 (IL-22) plays an important role in host immunity and tissue homeostasis in infectious and inflammatory diseases. However, the function and regulation of IL-22 in viral infection remain largely unknown. Here, we report that viral infection triggered early IL-22 production from the liver and lymphoid organs. γδ T cells are the main immune cells to produce IL-22 in the liver, a process mediated by the IL-23/phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. In the presence of IL-23, IL-22 production is independent of aryl hydrocarbon receptor (AhR) signaling. In acute and persistent viral infections, IL-22 deficiency resulted in thymic and splenic hypertrophy, while excessive IL-22 induced atrophy in these lymphoid organs. Moreover, IL-22 deficiency enhanced T cell responses to promote viral clearance, but increased IL-22 in vivo decreased T cell numbers and functions in the liver and lymphoid tissues. Together, our findings reveal a significant effect of the IL-23/PI3K/mTORC1 axis on regulating IL-22 production and also identify a novel role of IL-22 in controlling antiviral T cell responses in the non-lymphoid and lymphoid organs during acute and persistent viral infections.
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Objectives:The objective of this study was to conduct an umbrella review of therapeutic studies relevant to emergency medicine, analyzing patterns in effect size, power, and signals of potential bias across an entire field of clinical research. Methods:We combined topic-and journal-driven searches of PubMed and Google Scholar for published articles of systematic reviews and meta-analyses (SRMA) relevant to emergency medicine (last search in November 2020). Data were screened and extracted by six investigators. Redundant meta-analyses were removed. Whenever possible for each comparison we extracted one meta-analysis on mortality with the most events and one meta-analysis on a nonmortality outcome with the most studies.From each meta-analysis we extracted all individual study effects; outcomes were converted to odds ratios (ORs) and placed on a common scale where an OR < 1.0 represents a reduction in a harmful outcome with an experimental treatment versus control. Outcomes were analyzed at the level of individual studies and at the level of summary effects across meta-analyses.Results: A total of 332 articles contained 431 eligible meta-analyses with a total of 3,129 individual study outcomes; of these, 2,593 (83%) were from randomized controlled trials. The median OR across all studies was 0.70. Within each meta-analysis, the earliest study effect on average demonstrated larger benefit compared to the overall summary effect. Only 57 of 431 meta-analyses (13%) both favored the experimental intervention and did not show any signal of small study effects or excess significance, and of those only 12 had at least one study with 80% or higher power to detect an OR of 0.70. Of these, no interventions significantly decreased mortality in well-powered trials. Although the power of studies increased somewhat over time, the majority of studies were underpowered.Conclusions: Few interventions studied within SRMAs relevant to emergency medicine seem to have strong and unbiased evidence for improving outcomes. The field would benefit from more optimally powered trials.
e561 Background: pPRT increases local control, biochemical progression free survival, and even overall survival in patients with adverse features undergoing prostatectomy. The Radiation Therapy Oncology Group (RTOG) consensus definition of the clinical target volume (CTV) in 2010 was based on patterns of failure and anatomy without consideration of pre-operative imaging. This results in large volumes of bladder in the treatment field. Our study evaluates whether incorporation of pre-operative prostate volume can reduce the post-operative CTV and minimize dose to adjacent normal tissue. Methods: We reviewed records of all patients with available pre-operative pelvic CT scans treated at our institution with pPRT. The pre-operative CT scan was fused to the simulation CT. Post-operative CTV (CTV1) was delineated based on RTOG guidelines. A separate CTV (CTV2) was constructed, based on the intact prostate and proximal seminal vesicles. Plans were constructed for each CTV and doses to rectum, bladder, and penile bulb calculated, as well as concordance between the two CTVs and planning target volumes (PTVs). Paired student’s t-test was used to calculate difference between doses in the two different plans. Results: 10 patients’ plans were analyzed. Dosimetric parameters are shown in table 1. Volume of the bladder receiving 65 Gy or higher (V65) was significantly higher in CTV1. As would be expected, there were no significant differences in dose to either the rectum or penile bulb. Additionally, there was on average only 39% overlap between the CTVs and 60% between the PTVs in the two plans. Conclusions: Utilization of the pre-operative pelvic CT scan can aid in more accurate delineation of the CTV/PTV in prostate bed radiation therapy and decrease the bladder dose. As many patients at risk for pPRT have had this imaging performed preoperatively, in accordance with guidelines, incorporation of this data appears prudent. These findings need to be validated in a larger cohort. [Table: see text]
IL-22 is an important cytokine in modulating the consequences of inflammation in lesions, including the liver. However, the role of IL-22 in Lymphocytic Choriomeningitis Virus (LCMV)-induced viral hepatitis remains obscure. Here, we report that LCMV-induced IL-23 release promoted IL-22 production. And gdT cells and double negative T cells (DNT, CD3+ CD4− CD8− γδTCR− NK1.1−) were the main sources of IL-22 and IL-17 productions following LCMV infection in the liver. Interestingly, we also found that IL-23-stimulated IL-17 production in γδ T cells, and DNT cells were totally dependent on RORγt and PI3K/mTOR, but independent in AhR activities. Although IL-22 production in these two lymphocyte subsets depended on PI3K/mTOR, unlike IL-17 production, IL-22 production required additional signals from RORγt and AhR. Furthermore, IL-22 appeared to act as an important mediator in T cell responses in LCMV-induced viral hepatitis, despite the fact that the IL-22 receptor is restricted to being expressed on non-hematopoitic cells. IL-22−/− mice increased the recruitment of activated T cells to the liver and enhanced polyfunctional cytokine productions in effector CD4+ and CD8+ T cells in LCMV-induced acute or persistent viral hepatitis. Thus, our data revealed a novel connection between IL-23-PI3K/mTOR signaling pathway and the regulation of IL-22/IL-17 productions in the liver, and showed a novel role of IL-22 in modulating the plurifunctionality of anti-viral T cell responses during acute and persistent LCMV infection.
Dramatic cytoskeletal activities and protein movements are seen when T cells engage cognate targets or antigen presenting cells. These include formation of a specialized contact site known as the immunological synapse (IS), clustering of vesicles around the microtubule organizing center (MTOC) and translocation of the MTOC up to the IS. Ultimately, this leads to focused secretion towards the cognate target. In an effort to understand how MTOC translocation takes place, we have investigated the roles of dynein, p150Glued, Lis1,NDE1 and NDEL1 using Jurkat cells as a model system. Using expressed molecular traps aimed at dynein intermediate chain (DIC) or LC8 (a dynein light chain), and Jurkat cells expressing fluorescent CTLA-4 constructs targeting secretory vesicles, we have shown that dynein is required for both vesicle clustering and MTOC translocation. When p150Glued expression was reduced, vesicles became dispersed but MTOC translocation was unaffected suggesting that dynactin was needed for vesicle movements but not MTOC translocation. MTOC translocation was potently blocked when Lis1 expression was reduced. We also find that NDE1 accumulates at the IS and pulls down with DIC and Lis1. Overexpression of GFP-NDE1 blocks MTOC polarization. The combination of localization and functional data suggests that there are two separate dynein complexes, a dynein-Lis1-NDE1/NDEL complex that mediates MTOC translocation and a dynein-dynactin complex that mediates vesicle clustering.
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