Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin.

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is a critical enzyme in the mevalonate pathway that regulates the biosynthesis of cholesterol as well as isoprenoids that mediate the membrane association of certain GTPases. Blockade of this enzyme by atorvastatin (AT) inhibits the destructive proinflammatory T helper cell (Th)1 response during experimental autoimmune encephalomyelitis and may be beneficial in the treatment of multiple sclerosis and other Th1-mediated autoimmune diseases. Here we present evidence linking specific isoprenoid intermediates of the mevalonate pathway to signaling pathways that regulate T cell autoimmunity. We demonstrate that the isoprenoid geranylgeranyl-pyrophosphate (GGPP) mediates proliferation, whereas both GGPP and its precursor, farnesyl-PP, regulate the Th1 differentiation of myelin-reactive T cells. Depletion of these isoprenoid intermediates in vivo via oral AT administration hindered these T cell responses by decreasing geranylgeranylated RhoA and farnesylated Ras at the plasma membrane. This was associated with reduced extracellular signal-regulated kinase (ERK) and p38 phosphorylation and DNA binding of their cotarget c-fos in response to T cell receptor activation. Inhibition of ERK and p38 mimicked the effects of AT and induced a Th2 cytokine shift. Thus, by connecting isoprenoid availability to regulation of Th1/Th2 fate, we have elucidated a mechanism by which AT may suppress Th1-mediated central nervous system autoimmune disease

Peroxisome proliferator-activated receptor (PPAR)alpha expression in T cells mediates gender differences in development of T cell-mediated autoimmunity.

Peroxisome proliferator-activated receptor (PPAR)alpha is a nuclear receptor that mediates gender differences in lipid metabolism. PPARalpha also functions to control inflammatory responses by repressing the activity of nuclear factor kappaB (NF-kappaB) and c-jun in immune cells. Because PPARalpha is situated at the crossroads of gender and immune regulation, we hypothesized that this gene may mediate sex differences in the development of T cell-mediated autoimmune disease. We show that PPARalpha is more abundant in male as compared with female CD4(+) cells and that its expression is sensitive to androgen levels. Genetic ablation of this gene selectively removed the brake on NF-kappaB and c-jun activity in male T lymphocytes, resulting in higher production of interferon gamma and tumor necrosis factor (but not interleukin 17), and lower production of T helper (Th)2 cytokines. Upon induction of experimental autoimmune encephalomyelitis, male but not female PPARalpha(-/-) mice developed more severe clinical signs that were restricted to the acute phase of disease. These results suggest that males are less prone to develop Th1-mediated autoimmunity because they have higher T cell expression of PPARalpha

OGR1/GPR68 Modulates the Severity of Experimental Autoimmune Encephalomyelitis and Regulates Nitric Oxide Production by Macrophages.

Ovarian cancer G protein-coupled receptor 1 (OGR1) is a proton-sensing molecule that can detect decreases in extracellular pH that occur during inflammation. Although OGR1 has been shown to have pro-inflammatory functions in various diseases, its role in autoimmunity has not been examined. We therefore sought to determine whether OGR1 has a role in the development of T cell autoimmunity by contrasting the development of experimental autoimmune encephalomyelitis between wild type and OGR1-knockout mice. OGR1-knockout mice showed a drastically attenuated clinical course of disease that was associated with a profound reduction in the expansion of myelin oligodendrocyte glycoprotein 35-55-reactive T helper 1 (Th1) and Th17 cells in the periphery and a reduced accumulation of Th1 and Th17 effectors in the central nervous system. We determined that these impaired T cell responses in OGR1-knockout mice associated with a reduced frequency and number of dendritic cells in draining lymph nodes during EAE and a higher production of nitric oxide by macrophages. Our studies suggest that OGR1 plays a key role in regulating T cell responses during autoimmunity

Peroxisome proliferator-activated receptor delta limits the expansion of pathogenic Th cells during central nervous system autoimmunity.

Peroxisome proliferator-activated receptors (PPARs; PPAR-alpha, PPAR-delta, and PPAR-gamma) comprise a family of nuclear receptors that sense fatty acid levels and translate this information into altered gene transcription. Previously, it was reported that treatment of mice with a synthetic ligand activator of PPAR-delta, GW0742, ameliorates experimental autoimmune encephalomyelitis (EAE), indicating a possible role for this nuclear receptor in the control of central nervous system (CNS) autoimmune inflammation. We show that mice deficient in PPAR-delta (PPAR-delta(-/-)) develop a severe inflammatory response during EAE characterized by a striking accumulation of IFN-gamma(+)IL-17A(-) and IFN-gamma(+)IL-17A(+) CD4(+) cells in the spinal cord. The preferential expansion of these T helper subsets in the CNS of PPAR-delta(-/-) mice occurred as a result of a constellation of immune system aberrations that included higher CD4(+) cell proliferation, cytokine production, and T-bet expression and enhanced expression of IL-12 family cytokines by myeloid cells. We also show that the effect of PPAR-delta in inhibiting the production of IFN-gamma and IL-12 family cytokines is ligand dependent and is observed in both mouse and human immune cells. Collectively, these findings suggest that PPAR-delta serves as an important molecular brake for the control of autoimmune inflammation

Common garden experiments reveal uncommon responses across temperatures, locations, and species of ants

Population changes and shifts in geographic range boundaries induced by climate change have been documented for many insect species. On the basis of such studies, ecological forecasting models predict that, in the absence of dispersal and resource barriers, many species will exhibit large shifts in abundance and geographic range in response to warming. However, species are composed of individual populations, which may be subject to different selection pressures and therefore may be differentially responsive to environmental change. Asystematic responses across populations and species to warming will alter ecological communities differently across space. Common garden experiments can provide a more mechanistic understanding of the causes of compositional and spatial variation in responses to warming. Such experiments are useful for determining if geographically separated populations and co-occurring species respond differently to warming, and they provide the opportunity to compare effects of warming on fitness (survivorship and reproduction). We exposed colonies of two common ant species in the eastern United States, Aphaenogaster rudis and Temnothorax curvispinosus, collected along a latitudinal gradient from Massachusetts to North Carolina, to growth chamber treatments that simulated current and projected temperatures in central Massachusetts and central North Carolina within the next century. Regardless of source location, colonies of A. rudis, a keystone seed disperser, experienced high mortality and low brood production in the warmest temperature treatment. Colonies of T. curvispinosus from cooler locations experienced increased mortality in the warmest rearing temperatures, but colonies from the warmest locales did not. Our results suggest that populations of some common species may exhibit uniform declines in response to warming across their geographic ranges, whereas other species will respond differently to warming in different parts of their geographic ranges. Our results suggest that differential responses of populations and species must be incorporated into projections of range shifts in a changing climate.©2012 The Authors. Ecology and Evolution published by Blackwell Publishing Ltd

Using physiology to predict the responses of ants to climatic warming

Physiological intolerance of high temperatures places limits on organismal responses to the temperature increases associated with global climatic change. Because ants are geographically widespread, ecologically diverse, and thermophilic, they are an ideal system for exploring the extent to which physiological tolerance can predict responses to environmental change. Here, we expand on simple models that use thermal tolerance to predict the responses of ants to climatic warming. We investigated the degree to which changes in the abundance of ants under warming reflect reductions in the thermal niche space for their foraging. In an eastern deciduous forest system in the United States with approximately 40 ant species, we found that for some species, the loss of thermal niche space for foraging was related to decreases in abundance with increasing experimental climatic warming. However, many ant species exhibited no loss of thermal niche space. For one well-studied species, Temnothorax curvispinosus, we examined both survival of workers and growth of colonies (a correlate of reproductive output) as functions of temperature in the laboratory, and found that the range of thermal tolerances for colony growth was much narrower than for survival of workers. We evaluated these functions in the context of experimental climatic warming and found that the difference in the responses of these two attributes to temperature generates differences in the means and especially the variances of expected fitness under warming. The expected mean growth of colonies was optimized at intermediate levels of warming (24°C above ambient); yet, the expected variance monotonically increased with warming. In contrast, the expected mean and variance of the survival of workers decreased when warming exceeded 4°C above ambient. Together, these results for T. curvispinosus emphasize the importance of measuring reproduction (colony growth) in the context of climatic change: indeed, our examination of the loss of thermal niche space with the larger species pool could be missing much of the warming impact due to these analyses being based on survival rather than reproduction. We suggest that while physiological tolerance of temperature can be a useful predictive tool for modeling responses to climatic change, future efforts should be devoted to understanding the causes and consequences of variability in models of tolerance calibrated with different metrics of performance and fitness. © The Author 2013. All rights reserved

A Physiological Trait-Based Approach To Predicting The Responses Of Species To Experimental Climatic Warming

Physiological tolerance of environmental conditions can influence species-level responses to climatic change. Here, we used species-specific thermal tolerances to predict the community responses of ant species to experimental forest-floor warming at the northern and southern boundaries of temperate hardwood forests in eastern North America. We then compared the predictive ability of thermal tolerance versus correlative species distribution models (SDMs) which are popular forecasting tools for modeling the effects of climatic change. Thermal tolerances predicted the responses of 19 ant species to experimental climatic warming at the southern site, where environmental conditions are relatively close to the ants' upper thermal limits. In contrast, thermal tolerances did not predict the responses of the 6 species in the northern site, where environmental conditions are relatively far from the ants' upper thermal limits. Correlative SDMs were not predictive at either site. Our results suggest that, in environments close to a species' physiological limits, physiological trait-based measurements can successfully forecast the responses of species to future conditions. Although correlative SDMs may predict large-scale responses, such models may not be accurate for predicting site-level responses.Organismic and Evolutionary Biolog

A physiological trait-based approach to predicting the responses of species to experimental climate warming

Physiological tolerance of environmental conditions can influence species-level responses to climate change. Here, we used species-specific thermal tolerances to predict the community responses of ant species to experimental forest-floor warming at the northern and southern boundaries of temperate hardwood forests in eastern North America. We then compared the predictive ability of thermal tolerance vs. correlative species distribution models (SDMs) which are popular forecasting tools for modeling the effects of climate change. Thermal tolerances predicted the responses of 19 ant species to experimental climate warming at the southern site, where environmental conditions are relatively close to the ants\u27 upper thermal limits. In contrast, thermal tolerances did not predict the responses of the six species in the northern site, where environmental conditions are relatively far from the ants\u27 upper thermal limits. Correlative SDMs were not predictive at either site. Our results suggest that, in environments close to a species\u27 physiological limits, physiological trait-based measurements can successfully forecast the responses of species to future conditions. Although correlative SDMs may predict large-scale responses, such models may not be accurate for predicting sitelevel responses. © 2012 by the Ecological Society of America

Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo

Epidemiological studies show that patients with type 2 diabetes (T2DM) and individuals with a diabetes-independent elevation in blood glucose have an increased risk for developing dementia, specifically dementia due to Alzheimer’s disease (AD). These observations suggest that abnormal glucose metabolism likely plays a role in some aspects of AD pathogenesis, leading us to investigate the link between aberrant glucose metabolism, T2DM, and AD in murine models. Here, we combined two techniques — glucose clamps and in vivo microdialysis — as a means to dynamically modulate blood glucose levels in awake, freely moving mice while measuring real-time changes in amyloid-β (Aβ), glucose, and lactate within the hippocampal interstitial fluid (ISF). In a murine model of AD, induction of acute hyperglycemia in young animals increased ISF Aβ production and ISF lactate, which serves as a marker of neuronal activity. These effects were exacerbated in aged AD mice with marked Aβ plaque pathology. Inward rectifying, ATP-sensitive potassium (K(ATP)) channels mediated the response to elevated glucose levels, as pharmacological manipulation of K(ATP) channels in the hippocampus altered both ISF Aβ levels and neuronal activity. Taken together, these results suggest that K(ATP) channel activation mediates the response of hippocampal neurons to hyperglycemia by coupling metabolism with neuronal activity and ISF Aβ levels