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.

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