Endotoxin tolerance and cross-tolerance in mast cells involves TLR4, TLR2 and FcεR1 interactions and SOCS expression: perspectives on immunomodulation in infectious and allergic diseases

<p>Abstract</p> <p>Background</p> <p>The study of the endotoxin tolerance phenomenon in light of the recently defined roles of mast cells and toll-like receptors as essential components of the innate immune response and as orchestrators of acquired immunity may reveal potentially useful mechanisms of immunomodulation of infectious and allergic inflammatory responses, such as sepsis or asthma. Here we evaluated the phenomenon of direct tolerance of endotoxins, as well as the induction of cross-tolerance and synergism by stimulation with toll-like receptor-2 (TLR2) and FcεR1 agonists, in murine mast cells prestimulated with lipopolysaccharide (LPS). Additionally, we evaluated some stimulatory and inhibitory signaling molecules potentially involved in these phenomena.</p> <p>Methods</p> <p>MC/9 cells and primary bone marrow-derived mast cells obtained from C57BL/6 and TLR4^-/-knock-out mice were sensitized to DNP-HSA (antigen) by incubation with DNP-IgE and were prestimulated with LPS for 18 hr prior to stimulation. Cultures were stimulated with LPS or Pam3Cys-Ser-(Lys)4 3HCl (P3C), a TLR2 agonist, individually or in combination with antigen. The production of IL-6 and TNFα, the phosphorylation of NFκB and p38 MAPK, and the expression of TLR4 and SOCS-1 and -3 were analyzed.</p> <p>Results</p> <p>We found that production of TNFα and IL-6 in murine mast cells that have been pretreated with LPS and challenged with TLR4 (LPS) or -2 (P3C) agonists was reduced, phenomena described as endotoxin tolerance (LPS) and cross-tolerance (P3C), respectively. The expression of TLR4 was not affected by LPS pretreatment. Our results show that the FcεR1 agonist DNP-HSA (antigen) interacts synergistically with LPS or P3C to markedly enhance production of cytokines (TNFα and IL-6). This synergistic effect with LPS and P3C was also attenuated by LPS pretreatment and was mediated by TLR4. These results may be attributed to the reduction in phosphorylation of the mitogen-activated protein kinase (MAPK), p38, and the transcription factor NFκB, as well as to an increase in the expression of the suppressors of cytokine signaling (SOCS)-1 and -3 proteins in LPS-pretreated mast cells.</p> <p>Conclusions</p> <p>These findings can be explored with respect to the modulation of inflammatory responses associated with infectious and allergic processes in future studies.</p

rBMP Represses Wnt Signaling and Influences Skeletal Progenitor Cell Fate Specification During Bone Repair

Bone morphogenetic proteins (BMPs) participate in multiple stages of the fetal skeletogenic program from promoting cell condensation to regulating chondrogenesis and bone formation through endochondral ossification. Here, we show that these pleiotropic functions are recapitulated when recombinant BMPs are used to augment skeletal tissue repair. In addition to their well-documented ability to stimulate chondrogenesis in a skeletal injury, we show that recombinant BMPs (rBMPs) simultaneously suppress the differentiation of skeletal progenitor cells in the endosteum and bone marrow cavity to an osteoblast lineage. Both the prochondrogenic and antiosteogenic effects are achieved because rBMP inhibits endogenous β-catenin-dependent Wnt signaling. In the injured periosteum, this repression of Wnt activity results in sox9 upregulation; consequently, cells in the injured periosteum adopt a chondrogenic fate. In the injured endosteum, rBMP also inhibits Wnt signaling, which results in the runx2 and collagen type I downregulation; consequently, cells in this region fail to differentiate into osteoblasts. In muscle surrounding the skeletal injury site, rBMP treatment induces Smad phosphorylation followed by exuberant cell proliferation, an increase in alkaline phosphatase activity, and chondrogenic differentiation. Thus different populations of adult skeletal progenitor cells interpret the same rBMP stimulus in unique ways, and these responses mirror the pleiotropic effects of BMPs during fetal skeletogenesis. These mechanistic insights may be particularly useful for optimizing the reparative potential of rBMPs while simultaneously minimizing their adverse outcomes. © 2010 American Society for Bone and Mineral Research

Land-use change to bioenergy: grassland to short rotation coppice willow has an improved carbon balance

The effect of a transition from grassland to second-generation (2G) bioenergy on soil carbon and greenhouse gas (GHG) balance is uncertain, with limited empirical data on which to validate landscape-scale models, sustainability criteria and energy policies. Here, we quantified soil carbon, soil GHG emissions and whole ecosystem carbon balance for short rotation coppice (SRC) bioenergy willow and a paired grassland site, both planted at commercial scale. We quantified the carbon balance for a 2-year period and captured the effects of a commercial harvest in the SRC willow at the end of the first cycle. Soil fluxes of nitrous oxide (N2O) and methane (CH4) did not contribute significantly to the GHG balance of these land uses. Soil respiration was lower in SRC willow (912 ± 42 g C m−2 yr−1) than in grassland (1522 ± 39 g C m−2 yr−1). Net ecosystem exchange (NEE) reflected this with the grassland a net source of carbon with mean NEE of 119 ± 10 g C m−2 yr−1 and SRC willow a net sink, −620 ± 18 g C m−2 yr−1. When carbon removed from the ecosystem in harvested products was considered (Net Biome Productivity), SRC willow remained a net sink (221 ± 66 g C m−2 yr−1). Despite the SRC willow site being a net sink for carbon, soil carbon stocks (0–30 cm) were higher under the grassland. There was a larger NEE and increase in ecosystem respiration in the SRC willow after harvest; however, the site still remained a carbon sink. Our results indicate that once established, significant carbon savings are likely in SRC willow compared with the minimally managed grassland at this site. Although these observed impacts may be site and management dependent, they provide evidence that land-use transition to 2G bioenergy has potential to provide a significant improvement on the ecosystem service of climate regulation relative to grassland systems

Bone regeneration: current concepts and future directions

Bone regeneration is a complex, well-orchestrated physiological process of bone formation, which can be seen during normal fracture healing, and is involved in continuous remodelling throughout adult life. However, there are complex clinical conditions in which bone regeneration is required in large quantity, such as for skeletal reconstruction of large bone defects created by trauma, infection, tumour resection and skeletal abnormalities, or cases in which the regenerative process is compromised, including avascular necrosis, atrophic non-unions and osteoporosis. Currently, there is a plethora of different strategies to augment the impaired or 'insufficient' bone-regeneration process, including the 'gold standard' autologous bone graft, free fibula vascularised graft, allograft implantation, and use of growth factors, osteoconductive scaffolds, osteoprogenitor cells and distraction osteogenesis. Improved 'local' strategies in terms of tissue engineering and gene therapy, or even 'systemic' enhancement of bone repair, are under intense investigation, in an effort to overcome the limitations of the current methods, to produce bone-graft substitutes with biomechanical properties that are as identical to normal bone as possible, to accelerate the overall regeneration process, or even to address systemic conditions, such as skeletal disorders and osteoporosis

Simple mindreading abilities predict complex theory of mind: developmental delay in autism spectrum disorders

Theory of Mind (ToM) is impaired in individuals with Autism Spectrum Disorders (ASD). The aims of this study were to: i) examine the developmental trajectories of ToM abilities in two different mentalizing tasks in children with ASD compared to TD children; and ii) to assess if a ToM simple test known as Eyes-test could predict performance on the more advanced ToM task, i.e. Comic Strip test. Based on a sample of 37 children with ASD and 55 TD children, our results revealed slower development at varying rates in all ToM measures in children with ASD, with delayed onset compared to TD children. These results could stimulate new treatments for social abilities, which would lessen the social deficit in ASD

Sectoral dynamics of financial contagion in Europe - The cases of the recent crises episodes

In this paper, we investigate the existence of financial contagion in the European Union during the recent Global Financial Crisis (GFC) of 2007-2009 and the European Sovereign Debt Crisis (ESDC) that started in 2009. Our sample includes sectorial equity indices for 15 countries from 2004 to 2014. We adopt an ADCC-GJR-GARCH model for the time-varying correlations and a Markov-Switching model to identify the lead/lag relationship in crisis transition dates across the countries and the sectors. We assess the patterns of financial contagion by sector and by country. Our results support the existence of financial contagion in all business sectors under the GFC and the ESDC. Financials and Telecommunications are the most affected, while the Industrials and the Consumer Goods the least in each crisis respectively. Stock markets in the Core EU are the most affected in both crises. We find evidence of a non-synchronized transition of all countries to the crisis regime, in both crises. We believe that our results may provide useful insights for investors and policy makers

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Will the crisis "tear us apart"? Evidence from the EU

We examine the synchronisation of the European Union (EU) financial markets before and during the 2007 global financial crisis. We use an Asymmetric Dynamic Conditional Correlation (ADCC)-GARCH framework to control for the time-varying correlations and a Markov-Switching model to identify regime changes. Our sample considers 27 EU nations for the period 2000-2011. For each nation we formulate several characteristics of the crisis such as, synchronicity, duration and intensity measures. We find that the more recent EU members had a lagged entry to the crisis regime, were less adversely affected, show higher correlation between their stock markets and have their credit scores being revised more frequently relative to established EU members. We also find that higher levels of sovereign debt and lower levels of industrialisation positively impact crisis duration and intensity. Our results refute the notion of uniform integration of EU financial markets as evident from the highly non-synchronised observed crisis experience among the EU members. As such, one-size fits all policies are likely to be ineffective

Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21276-3</jats:p