Interleukin 10 (IL-10) is an anti-inflammatory cytokine that plays a critical role in the control of immune responses. However, its mechanisms of action remain poorly understood. Here, we show that ...IL-10 opposes the switch to the metabolic program induced by inflammatory stimuli in macrophages. Specifically, we show that IL-10 inhibits lipopolysaccharide-induced glucose uptake and glycolysis and promotes oxidative phosphorylation. Furthermore, IL-10 suppresses mammalian target of rapamycin (mTOR) activity through the induction of an mTOR inhibitor, DDIT4. Consequently, IL-10 promotes mitophagy that eliminates dysfunctional mitochondria characterized by low membrane potential and a high level of reactive oxygen species. In the absence of IL-10 signaling, macrophages accumulate damaged mitochondria in a mouse model of colitis and inflammatory bowel disease patients, and this results in dysregulated activation of the NLRP3 inflammasome and production of IL-1β.
Interstitial osmolality is a key homeostatic variable that varies depending on the tissue microenvironment. Mammalian cells have effective mechanisms to cope with osmotic stress by engaging various ...adaptation responses. Hyperosmolality due to high dietary salt intake has been linked to pathological inflammatory conditions. Little is known about the mechanisms of sensing the hyperosmotic stress by the innate immune system. Here we report that caspase-1 is activated in macrophages under hypertonic conditions. Mice with high dietary salt intake display enhanced induction of Th17 response upon immunization, and this effect is abolished in caspase-1-deficient mice. Our findings identify an unknown function of the inflammasome as a sensor of hyperosmotic stress, which is crucial for the induction of inflammatory Th17 response.
Mannose-binding lectin and innate immunity Eddie Ip, W.K; Takahashi, Kazue; Alan Ezekowitz, R ...
Immunological reviews,
July 2009, Volume:
230, Issue:
1
Journal Article
Peer reviewed
Innate immunity is the earliest response to invading microbes and acts to contain infection in the first minutes to hours of challenge. Unlike adaptive immunity that relies upon clonal expansion of ...cells that emerge days after antigenic challenge, the innate immune response is immediate. Soluble mediators, including complement components and the mannose binding lectin (MBL) make an important contribution to innate immune protection and work along with epithelial barriers, cellular defenses such as phagocytosis, and pattern-recognition receptors that trigger pro-inflammatory signaling cascades. These four aspects of the innate immune system act in concert to protect from pathogen invasion. Our work has focused on understanding the protection provided by this complex defense system and, as discussed in this review, the particular contribution of soluble mediators such as MBL and phagocytic cells. Over the past two decades both human epidemiological data and mouse models have indicated that MBL plays a critical role in innate immune protection against a number of pathogens. As demonstrated by our recent in vitro work, we show that MBL and the innate immune signaling triggered by the canonical pattern-recognition receptors (PRRs), the Toll-like receptors (TLRs), are linked by their spatial localization to the phagosome. These observations demonstrated a novel role for MBL as a TLR co-receptor and establishes a new paradigm for the role of opsonins, which we propose to function not only to increase microbial uptake but also to spatially coordinate, amplify, and synchronize innate immune defenses mechanism. In this review we discuss both the attributes of MBL that make it a unique soluble pattern recognition molecule and also highlight its broader role in coordinating innate immune activation.
Abstract
In the magnetohydrodynamic (MHD) perspective, the planet’s bow shock would disappear when the fast-mode Mach number (
M
F
) of the solar wind is less than one. Compared to Earth, Mercury is ...subject to a lower
M
F
solar wind due to its proximity to the Sun, resulting in a higher possibility of the disappearance of its bow shock. To examine the variability of Mercury’s bow shock in response to the solar wind properties, analyses of the observations by the Helios spacecraft at 0.30–0.50 au during 1975–1983, covering solar cycle 21, together with the theoretical solutions and MHD simulations are conducted in this study. Our observational analyses show that more solar wind data with extremely low fast-mode Mach numbers (say,
M
F
≤ 1.5) are observed during the rising and maximum phases and are characterized by a significantly low proton number density. It is also found that approximately 35% of the extremely low fast-mode Mach number solar wind events (
M
F
≤ 1.5) occur within the main body of interplanetary coronal mass ejections (ICMEs), while about 58% of them are unrelated to ICMEs. Three of these events are selected to demonstrate that the occurrences of the solar wind with
M
F
≤ 1.5 may not be necessarily affected by ICMEs. Our theoretical and numerical results indicate that when Mercury encounters the solar wind with
M
F
≤ 1.5, its bow shock would move farther away, become flattened, and even disappear. Furthermore, our calculations suggest that Mercury’s bow shock would become a slow-mode shock with a concave-upward structure under such extreme solar wind conditions.
The Rosetta spacecraft has investigated comet 67P/Churyumov-Gerasimenko from large heliocentric distances to its perihelion passage and beyond. We trace the seasonal and diurnal evolution of the ...colors of the 67P nucleus, finding changes driven by sublimation and recondensation of water ice. The whole nucleus became relatively bluer near perihelion, as increasing activity removed the surface dust, implying that water ice is widespread underneath the surface. We identified large (1500 square meters) ice-rich patches appearing and then vanishing in about 10 days, indicating small-scale heterogeneities on the nucleus. Thin frosts sublimating in a few minutes are observed close to receding shadows, and rapid variations in color are seen on extended areas close to the terminator. These cyclic processes are widespread and lead to continuously, slightly varying surface properties.
Phagocytosis is a fundamental cellular process that is pivotal for immunity as it coordinates microbial killing, innate immune activation and antigen presentation. An essential step in this process ...is phagosome acidification, which regulates many functions of these organelles that allow phagosomes to participate in processes that are essential to both innate and adaptive immunity. Here we report that acidification of phagosomes containing Gram-positive bacteria is regulated by the NLRP3 inflammasome and caspase-1. Active caspase-1 accumulates on phagosomes and acts locally to control the pH by modulating buffering by the NADPH oxidase NOX2. These data provide insight into a mechanism by which innate immune signals can modify cellular defenses and establish a new function for the NLRP3 inflammasome and caspase-1 in host defense.
Early life environmental exposure, particularly during perinatal period, can have a life-long impact on organismal development and physiology. The biological rationale for this phenomenon is to ...promote physiological adaptations to the anticipated environment based on early life experience. However, perinatal exposure to adverse environments can also be associated with adult-onset disorders. Multiple environmental stressors induce glucocorticoids, which prompted us to investigate their role in developmental programming. Here, we report that perinatal glucocorticoid exposure had long-term consequences and resulted in diminished CD8 T cell response in adulthood and impaired control of tumor growth and bacterial infection. We found that perinatal glucocorticoid exposure resulted in persistent alteration of the hypothalamic-pituitary-adrenal (HPA) axis. Consequently, the level of the hormone in adults was significantly reduced, resulting in decreased CD8 T cell function. Our study thus demonstrates that perinatal stress can have long-term consequences on CD8 T cell immunity by altering HPA axis activity.
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•Early-life stress has a long-term effect on the immune system•Perinatal glucocorticoids exposure changes the set-point of the HPA axis•Reduced GR signaling decreases CD8 T cell function by altering chromatin at key loci•Perinatal glucocorticoids result in susceptibility to tumors and bacterial infection
Early life glucocorticoid exposure has long-term effects on immunity, including diminished CD8+ T cell responses in adulthood and impaired control of tumor growth as well as infection.
From an analysis of the long cadence light curves of M and K dwarfs obtained by the K2 observations, 3589 flares on 548 M dwarfs and 1647 flares on 343 K dwarfs have been identified. We compared the ...M and K dwarfs' flares with the G dwarfs' flares reported by Shibayama et al. The later type stars' flare occurrence frequencies are higher than those of the earlier type stars, but the earlier type stars produce more powerful flares than those of the later type stars. For the stars of all spectral types, the flare activities, including the flare energy, peak amplitude, and percentage of magnetic activity, increase with faster rotation of stars. The longer the flare duration is, the more energy the flare releases, but an upper limit exists. The saturation energy of M, K, and G dwarfs are derived to be about 1 × 1035 erg, 4 × 1035 erg and 1 × 1036 erg, respectively, in the present study. We estimated the power-law indices of the flare frequency distributions of three spectral type stars. They are 1.82 0.02 (M dwarfs) and 1.86 0.02 (K dwarfs) in comparison to the 2.01 0.03 for the G dwarfs found by Shibayama et al. For stars with Prot ≤ 10 days, they are 1.78 0.02 (M dwarfs), 1.82 0.03 (K dwarfs), and 2.09 0.04 (G dwarfs). The power-law indices of flare frequency distributions of the fast-rotating M- and K-type stars are nearly the same. This indicates that the flare or magnetic mechanisms of different types of low-mass stars may be similar in some sense.
Context. We investigate the formation and evolution of comet nuclei and other trans-Neptunian objects (TNOs) in the solar nebula and primordial disk prior to the giant planet orbit instability ...foreseen by the Nice model. Aims. Our goal is to determine whether most observed comet nuclei are primordial rubble-pile survivors that formed in the solar nebula and young primordial disk or collisional rubble piles formed later in the aftermath of catastrophic disruptions of larger parent bodies. We also propose a concurrent comet and TNO formation scenario that is consistent with observations. Methods. We used observations of comet 67P/Churyumov-Gerasimenko by the ESA Rosetta spacecraft, particularly by the OSIRIS camera system, combined with data from the NASA Stardust sample-return mission to comet 81P/Wild 2 and from meteoritics; we also used existing observations from ground or from spacecraft of irregular satellites of the giant planets, Centaurs, and TNOs. We performed modeling of thermophysics, hydrostatics, orbit evolution, and collision physics. Results. We find that thermal processing due to short-lived radionuclides, combined with collisional processing during accretion in the primordial disk, creates a population of medium-sized bodies that are comparably dense, compacted, strong, heavily depleted in supervolatiles like CO and CO2; they contain little to no amorphous water ice, and have experienced extensive metasomatism and aqueous alteration due to liquid water. Irregular satellites Phoebe and Himalia are potential representatives of this population. Collisional rubble piles inherit these properties from their parents. Contrarily, comet nuclei have low density, high porosity, weak strength, are rich in supervolatiles, may contain amorphous water ice, and do not display convincing evidence of in situ metasomatism or aqueous alteration. We outline a comet formation scenario that starts in the solar nebula and ends in the primordial disk, that reproduces these observed properties, and additionally explains the presence of extensive layering on 67P/Churyumov-Gerasimenko (and on 9P/Tempel 1 observed by Deep Impact), its bi-lobed shape, the extremely slow growth of comet nuclei as evidenced by recent radiometric dating, and the low collision probability that allows primordial nuclei to survive the age of the solar system. Conclusions. We conclude that observed comet nuclei are primordial rubble piles, and not collisional rubble piles. We argue that TNOs formed as a result of streaming instabilities at sizes below ~400 km and that ~350 of these grew slowly in a low-mass primordial disk to the size of Triton, Pluto, and Eris, causing little viscous stirring during growth. We thus propose a dynamically cold primordial disk, which prevented medium-sized TNOs from breaking into collisional rubble piles and allowed the survival of primordial rubble-pile comets. We argue that comets formed by hierarchical agglomeration out of material that remained after TNO formation, and that this slow growth was a necessity to avoid thermal processing by short-lived radionuclides that would lead to loss of supervolatiles, and that allowed comet nuclei to incorporate ~3 Myr old material from the inner solar system.
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