Novel role for the innate immune receptor toll-like receptor 4 (TLR4) in the regulation of the wnt signaling pathway and photoreceptor apoptosis

Recent evidence has implicated innate immunity in regulating neuronal survival in the brain during stroke and other neurodegenerations. Photoreceptors are specialized light-detecting neurons in the retina that are essential for vision. In this study, we investigated the role of the innate immunity receptor TLR4 in photoreceptors. TLR4 activation by lipopolysaccharide (LPS) significantly reduced the survival of cultured mouse photoreceptors exposed to oxidative stress. With respect to mechanism, TLR4 suppressed Wnt signaling, decreased phosphorylation and activation of the Wnt receptor LRP6, and blocked the protective effect of the Wnt3a ligand. Paradoxically, TLR4 activation prior to oxidative injury protected photoreceptors, in a phenomenon known as preconditioning. Expression of TNFα and its receptors TNFR1 and TNFR2 decreased during preconditioning, and preconditioning was mimicked by TNFα antagonists, but was independent of Wnt signaling. Therefore, TLR4 is a novel regulator of photoreceptor survival that acts through the Wnt and TNFα pathways. © 2012 Yi et al

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

The Effects of Biogeography on Ant Diversity and Activity on the Boston Harbor Islands, Massachusetts, U.S.A

Many studies have examined how island biogeography affects diversity on the scale of island systems. In this study, we address how diversity varies over very short periods of time on individual islands. To do this, we compile an inventory of the ants living in the Boston Harbor Islands National Recreation Area, Boston, Massachusetts, USA using data from a five-year All Taxa Biodiversity Inventory of the region's arthropods. Consistent with the classical theory of island biogeography, species richness increased with island size, decreased with island isolation, and remained relatively constant over time. Additionally, our inventory finds that almost half of the known Massachusetts ant fauna can be collected in the BHI, and identifies four new species records for Massachusetts, including one new to the United States, Myrmica scabrinodis. We find that the number of species actually active on islands depended greatly on the timescale under consideration. The species that could be detected during any given week of sampling could by no means account for total island species richness, even when correcting for sampling effort. Though we consistently collected the same number of species over any given week of sampling, the identities of those species varied greatly between weeks. This variation does not result from local immigration and extinction of species, nor from seasonally-driven changes in the abundance of individual species, but rather from weekly changes in the distribution and activity of foraging ants. This variation can be upwards of 50% of ant species per week. This suggests that numerous ant species on the BHI share the same physical space at different times. This temporal partitioning could well explain such unexpectedly high ant diversity in an isolated, urban site

Regional disparities in the beneficial effects of rising CO2 concentrations on crop water productivity

Rising atmospheric CO2 concentrations ([CO2]) are expected to enhance photosynthesis and reduce crop water use1. However, there is high uncertainty about the global implications of these effects for future crop production and agricultural water requirements under climate change. Here we combine results from networks of field experiments1, 2 and global crop models3 to present a spatially explicit global perspective on crop water productivity (CWP, the ratio of crop yield to evapotranspiration) for wheat, maize, rice and soybean under elevated [CO2] and associated climate change projected for a high-end greenhouse gas emissions scenario. We find CO2 effects increase global CWP by 10[0;47]%–27[7;37]% (median[interquartile range] across the model ensemble) by the 2080s depending on crop types, with particularly large increases in arid regions (by up to 48[25;56]% for rainfed wheat). If realized in the fields, the effects of elevated [CO2] could considerably mitigate global yield losses whilst reducing agricultural consumptive water use (4–17%). We identify regional disparities driven by differences in growing conditions across agro-ecosystems that could have implications for increasing food production without compromising water security. Finally, our results demonstrate the need to expand field experiments and encourage greater consistency in modelling the effects of rising [CO2] across crop and hydrological modelling communities

Physical and land-cover variables influence ant functional groups and species diversity along elevational gradients

Of particular importance in shaping species assemblages is the spatial heterogeneity of the environment. The aim of our study was to investigate the influence of spatial heterogeneity and environmental complexity on the distribution of ant functional groups and species diversity along altitudinal gradients in a temperate ecosystem (Pyrenees Mountains). During three summers, we sampled 20 sites distributed across two Pyrenean valleys ranging in altitude from 1,009 to 2,339 m by using pitfall traps and hand collection. The environment around each sampling points was characterized by using both physical and land-cover variables. We then used a self-organizing map algorithm (SOM, neural network) to detect and characterize the relationship between the spatial distribution of ant functional groups, species diversity, and the variables measured. The use of SOM allowed us to reduce the apparent complexity of the environment to five clusters that highlighted two main gradients: an altitudinal gradient and a gradient of environmental closure. The composition of ant functional groups and species diversity changed along both of these gradients and was differently affected by environmental variables. The SOM also allowed us to validate the contours of most ant functional groups by highlighting the response of these groups to the environmental and land-cover variables

The impact of single and pairwise Toll-like receptor activation on neuroinflammation and neurodegeneration

Background Toll-like receptors (TLRs) enable innate immune cells to respond to pathogen- and host-derived molecules. The central nervous system (CNS) exhibits most of the TLRs identified with predominant expression in microglia, the major immune cells of the brain. Although individual TLRs have been shown to contribute to CNS disorders, the consequences of multiple activated TLRs on the brain are unclear. We therefore systematically investigated and compared the impact of sole and pairwise TLR activation on CNS inflammation and injury. Methods Selected TLRs expressed in microglia and neurons were stimulated with their specific TLR ligands in varying combinations. Cell cultures were then analyzed by immunocytochemistry, FlowCytomix, and ELISA. To determine neuronal injury and neuroinflammation in vivo, C57BL/6J mice were injected intrathecally with TLR agonists. Subsequently, brain sections were analyzed by quantitative real-time PCR and immunohistochemistry. Results Simultaneous stimulation of TLR4 plus TLR2, TLR4 plus TLR9, and TLR2 plus TLR9 in microglia by their respective specific ligands results in an increased inflammatory response compared to activation of the respective single TLR in vitro. In contrast, additional activation of TLR7 suppresses the inflammatory response mediated by the respective ligands for TLR2, TLR4, or TLR9 up to 24 h, indicating that specific combinations of activated TLRs individually modulate the inflammatory response. Accordingly, the composition of the inflammatory response pattern generated by microglia varies depending on the identity and combination of the activated TLRs engaged. Likewise, neuronal injury occurs in response to activation of only selected TLRs and TLR combinations in vitro. Activation of TLR2, TLR4, TLR7, and TLR9 in the brain by intrathecal injection of the respective TLR ligand into C57BL/6J mice leads to specific expression patterns of distinct TLR mRNAs in the brain and causes influx of leukocytes and inflammatory mediators into the cerebrospinal fluid to a variable extent. Also, the intensity of the inflammatory response and neurodegenerative effects differs according to the respective activated TLR and TLR combinations used in vivo. Conclusions Sole and pairwise activation of TLRs modifies the pattern and extent of inflammation and neurodegeneration in the CNS, thereby enabling innate immunity to take account of the CNS diseases’ diversity

Down-Regulated NOD2 by Immunosuppressants in Peripheral Blood Cells in Patients with SLE Reduces the Muramyl Dipeptide-Induced IL-10 Production

Pattern recognition receptors (PRRs) such as Toll-like receptors are aberrantly expressed of peripheral blood mononuclear cells (PBMCs) in systemic lupus erythematosus (SLE) patients, for playing immunopathological roles. basal productions of cytokines (IL-6, IL-8 and IL-10) were significantly increased in immunosuppressant naïve patients and patients with active disease despite immunosuppressants compared with HCs. Upon MDP stimulaiton, relative induction (%) of cytokines (IL-1β) from PBMC was significantly increased in immunosuppressant naïve patients with inactive disease, and patients with active disease despite immunosuppressant treatment compared with HCs. Immunosuppressant usage was associated with a decreased basal production and MDP induced relative induction (%) of IL-10 in patients with inactive disease compared with immunosuppressant naïve patients and HCs.Bacterial exposure may increase the NOD2 expression in monocytes in immunosuppressant naïve SLE patients which can subsequently lead to aberrant activation of PBMCs to produce proinflammatory cytokines, implicating the innate immune response for extracellular pathogens in the immunopathological mechanisms in SLE. Immunosuppressant therapy may downregulate NOD2 expression in CD8+ T lymphocytes, monocytes, and DCs in SLE patients which subsequently IL-10 reduction, contributing towards the regulation of immunopathological mechanisms of SLE, at the expense of increasing risk of bacterial infection

Preconditioning-induced ischemic tolerance: a window into endogenous gearing for cerebroprotection

Ischemic tolerance defines transient resistance to lethal ischemia gained by a prior sublethal noxious stimulus (i.e., preconditioning). This adaptive response is thought to be an evolutionarily conserved defense mechanism, observed in a wide variety of species. Preconditioning confers ischemic tolerance if not in all, in most organ systems, including the heart, kidney, liver, and small intestine. Since the first landmark experimental demonstration of ischemic tolerance in the gerbil brain in early 1990's, basic scientific knowledge on the mechanisms of cerebral ischemic tolerance increased substantially. Various noxious stimuli can precondition the brain, presumably through a common mechanism, genomic reprogramming. Ischemic tolerance occurs in two temporally distinct windows. Early tolerance can be achieved within minutes, but wanes also rapidly, within hours. Delayed tolerance develops in hours and lasts for days. The main mechanism involved in early tolerance is adaptation of membrane receptors, whereas gene activation with subsequent de novo protein synthesis dominates delayed tolerance. Ischemic preconditioning is associated with robust cerebroprotection in animals. In humans, transient ischemic attacks may be the clinical correlate of preconditioning leading to ischemic tolerance. Mimicking the mechanisms of this unique endogenous protection process is therefore a potential strategy for stroke prevention. Perhaps new remedies for stroke are very close, right in our cells