Salmonella flagellin activates NAIP/NLRC4 and canonical NLRP3 inflammasomes in human macrophages

Infection of human macrophages with Salmonella enterica serovar Typhimurium (S. Typhimurium) leads to inflammasome activation. Inflammasomes are multi-protein complexes facilitating caspase–1 activation and subsequent gasdermin D-mediated cell death and interleukin–1β and interleukin–18 cytokine release. The NAIP/NLRC4 inflammasome is activated by multiple bacterial protein ligands including flagellin from the flagellum and the needle protein PrgI from the S. Typhimurium type III secretion system. Here we show that transfected ultrapure flagellin from S. Typhimurium induced cell death and cytokine secretion in THP–1 cells and primary human monocyte-derived macrophages (hMDM). In THP–1 cells, NAIP/NLRC4 and NLRP3 played redundant roles in inflammasome activation during infection with S. Typhimurium. Knock-out of NAIP or NLRC4 in THP–1 cells revealed that flagellin, but not PrgI, now activated the NLRP3 inflammasome through a ROS- and/or cathepsin-dependent mechanism that was independent of caspase–4/5 activity. In conclusion, our data suggest that NLRP3 can be activated by flagellin to act as a “safety net” to maintain inflammasome activation under conditions of suboptimal NAIP/NLRC4 activation, as observed in THP–1 cells, possibly explaining the redundant role of NLRP3 and NAIP/NLRC4 during S. Typhimurium infection.Wellcome Trus

IL-1α cleavage by inflammatory caspases of the noncanonical inflammasome controls the senescence-associated secretory phenotype.

Interleukin-1 alpha (IL-1α) is a powerful cytokine that modulates immunity, and requires canonical cleavage by calpain for full activity. Mature IL-1α is produced after inflammasome activation and during cell senescence, but the protease cleaving IL-1α in these contexts is unknown. We show IL-1α is activated by caspase-5 or caspase-11 cleavage at a conserved site. Caspase-5 drives cleaved IL-1α release after human macrophage inflammasome activation, while IL-1α secretion from murine macrophages only requires caspase-11, with IL-1β release needing caspase-11 and caspase-1. Importantly, senescent human cells require caspase-5 for the IL-1α-dependent senescence-associated secretory phenotype (SASP) in vitro, while senescent mouse hepatocytes need caspase-11 for the SASP-driven immune surveillance of senescent cells in vivo. Together, we identify IL-1α as a novel substrate of noncanonical inflammatory caspases and finally provide a mechanism for how IL-1α is activated during senescence. Thus, targeting caspase-5 may reduce inflammation and limit the deleterious effects of accumulated senescent cells during disease and Aging.Work was funded by British Heart Foundation grants FS/13/3/30038, FS/18/19/33371 and RG/16/8/32388 (MC); Cancer Research UK Cambridge Institute Core Grant C14303/A17197, Medical Research Council grants MR/M013049/1 and MR/R010013/1 (MN); and the Cambridge NIHR Biomedical Research Centre

3-D Photoionization Structure and Distances of Planetary Nebulae II. Menzel 1

We present the results of a spatio-kinematic study of the planetary nebula Menzel 1 using spectro-photometric mapping and a 3-D photoionization code. We create several 2-D emission line images from our long-slit spectra, and use these to derive the line fluxes for 15 lines, the Halpha/Hbeta extinction map, and the [SII] line ratio density map of the nebula. We use our photoionization code constrained by these data to derive the three-dimensional nebular structure and ionizing star parameters of Menzel 1 by simultaneously fitting the integrated line intensities, the density map, and the observed morphologies in several lines, as well as the velocity structure. Using theoretical evolutionary tracks of intermediate and low mass stars, we derive a mass for the central star of 0.63+-0.05 Msolar. We also derive a distance of 1050+_150 pc to Menzel 1.Comment: To be published in ApJ of 10th February 2005. 12 figure

Dendritic Cell-Derived TSLP Negatively Regulates HIF-1α and IL-1β during Dectin-1 signaling

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Thymic stromal lymphopoietin (TSLP) is a functionally pleotropic cytokine important in immune regulation, and TSLP dysregulation is associated with numerous diseases. TSLP is produced by many cell types, but has predominantly been characterized as a secreted factor from epithelial cells which activates dendritic cells (DC) that subsequently prime T helper (TH) 2 immunity. However, DC themselves make significant amounts of TSLP in response to microbial products, but the functional role of DC-derived TSLP remains unclear. We show that TSLPR signaling negatively regulates IL-1β production during dectin-1 stimulation of human DC. This regulatory mechanism functions by dampening Syk phosphorylation and is mediated via NADPH oxidase-derived ROS, HIF-1α and pro-IL-1β expression. Considering the profound effect TSLPR signaling has on the metabolic status and the secretome of dectin-1 stimulated DC, these data suggest that autocrine TSLPR signaling could have a fundamental role in modulating immunological effector responses at sites removed from epithelial cell production of TSLP

Dendritic Cell-Derived TSLP Negatively Regulates HIF-1α and IL-1β During Dectin-1 Signaling

Thymic stromal lymphopoietin (TSLP) is a functionally pleotropic cytokine important in immune regulation, and TSLP dysregulation is associated with numerous diseases. TSLP is produced by many cell types, but has predominantly been characterized as a secreted factor from epithelial cells which activates dendritic cells (DC) that subsequently prime T helper (TH) 2 immunity. However, DC themselves make significant amounts of TSLP in response to microbial products, but the functional role of DC-derived TSLP remains unclear. We show that TSLPR signaling negatively regulates IL-1β production during dectin-1 stimulation of human DC. This regulatory mechanism functions by dampening Syk phosphorylation and is mediated via NADPH oxidase-derived ROS, HIF-1α and pro-IL-1β expression. Considering the profound effect TSLPR signaling has on the metabolic status and the secretome of dectin-1 stimulated DC, these data suggest that autocrine TSLPR signaling could have a fundamental role in modulating immunological effector responses at sites removed from epithelial cell production of TSLP

High C3 photosynthetic capacity and high intrinsic water use efficiency underlies the high productivity of the bioenergy grass Arundo donax

AbstractArundo donax has attracted interest as a potential bioenergy crop due to a high apparent productivity. It uses C3 photosynthesis yet appears competitive with C4 grass biomass feedstock’s and grows in warm conditions where C4 species might be expected to be that productive. Despite this there has been no systematic study of leaf photosynthetic properties. This study determines photosynthetic and photorespiratory parameters for leaves in a natural stand of A. donax growing in southern Portugal. We hypothesise that A. donax has a high photosynthetic potential in high and low light, stomatal limitation to be small and intrinsic water use efficiency unusually low. High photosynthetic rates in A. donax resulted from a high capacity for both maximum Rubisco (Vc,max 117 μmol CO2 m−2 s−1) and ribulose-1:5-bisphosphate limited carboxylation rate (Jmax 213 μmol CO2 m−2 s−1) under light-saturated conditions. Maximum quantum yield for light-limited CO2 assimilation was also high relative to other C3 species. Photorespiratory losses were similar to other C3 species under the conditions of measurement (25%), while stomatal limitation was high (0.25) resulting in a high intrinsic water use efficiency. Overall the photosynthetic capacity of A. donax is high compared to other C3 species and comparable to C4 bioenergy grasses.</jats:p

Living for the weekend: youth identities in northeast England

Consumption and consumerism are now accepted as key contexts for the construction of youth identities in de-industrialized Britain. This article uses empirical evidence from interviews with young people to suggest that claims of `new community' are overstated, traditional forms of friendship are receding, and increasingly atomized and instrumental youth identities are now being culturally constituted and reproduced by the pressures and anxieties created by enforced adaptation to consumer capitalism. Analysis of the data opens up the possibility of a critical rather than a celebratory exploration of the wider theoretical implications of this process