The hemoglobin (Hb) scavenger receptor, CD163, is a macrophage-specific protein and the upregulated expression of this receptor is one of the major changes in the macrophage switch to alternative ...activated phenotypes in inflammation. Accordingly, a high CD163 expression in macrophages is a characteristic of tissues responding to inflammation. The scavenging of the oxidative and proinflammatory Hb leading to stimulation of the heme-oxygenase-1 and production of anti-inflammatory heme metabolites indicates that CD163 thereby indirectly contributes to the anti-inflammatory response.
In addition to this biological role in inflammation, CD163 is a potential inflammation biomarker and a therapeutic target. The biomarker form of CD163 is the soluble plasma CD163 that arises from the increased shedding of CD163 mediated by the tumor necrosis factor-α (TNF-α) cleaving enzyme. This explains that a steadily increasing literature documents that the plasma level of soluble CD163 is increased in a large spectrum of acute and chronic inflammatory disorders. The nonshed membrane form of CD163 in macrophages constitutes a target for drugs to be directed to macrophages in inflammation. This approach has been used in an animal inflammation model to highly increase the apparent therapeutic index of anti-inflammatory glucocorticoid drug that was coupled to an anti-CD163 antibody. Furthermore, other recent animal data, which indirectly involve CD163 in macrophages, demonstrate that injections of haptoglobin attenuate Hb-induced damages after blood transfusion.
The diagnostic and therapeutic properties of CD163 await further clinical studies and regulatory approval before implementation in the clinic.
The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell-type-specific transcriptional programs and responses to extracellular ...cues. Systematic mapping of functional enhancers and their biological contexts is required to understand the mechanisms by which variation in non-coding genetic sequences contributes to disease. Functional enhancers can be mapped by genomic sequence disruption, but this approach is limited to the subset of enhancers that are necessary in the particular cellular context being studied. We hypothesized that recruitment of a strong transcriptional activator to an enhancer would be sufficient to drive target gene expression, even if that enhancer was not currently active in the assayed cells. Here we describe a discovery platform that can identify stimulus-responsive enhancers for a target gene independent of stimulus exposure. We used tiled CRISPR activation (CRISPRa) to synthetically recruit a transcriptional activator to sites across large genomic regions (more than 100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA. We identified several CRISPRa-responsive elements with chromatin features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours an autoimmunity risk variant. Using engineered mouse models, we found that sequence perturbation of the disease-associated Il2ra enhancer did not entirely block Il2ra expression, but rather delayed the timing of gene activation in response to specific extracellular signals. Enhancer deletion skewed polarization of naive T cells towards a pro-inflammatory T helper (T
17) cell state and away from a regulatory T cell state. This integrated approach identifies functional enhancers and reveals how non-coding variation associated with human immune dysfunction alters context-specific gene programs.
Cell-mediated immunity critically depends on the localization of lymphocytes at sites of infection. While some memory T cells recirculate, a distinct lineage (resident memory T cells (T(RM) cells)) ...are embedded in nonlymphoid tissues (NLTs) and mediate potent protective immunity. However, the defining transcriptional basis for the establishment of T(RM) cells is unknown. We found that CD8(+) T(RM) cells lacked expression of the transcription factor KLF2 and its target gene S1pr1 (which encodes S1P1, a receptor for sphingosine 1-phosphate). Forced expression of S1P1 prevented the establishment of T(RM) cells. Cytokines that induced a T(RM) cell phenotype (including transforming growth factor-β (TGF-β), interleukin 33 (IL-33) and tumor-necrosis factor) elicited downregulation of KLF2 expression in a pathway dependent on phosphatidylinositol-3-OH kinase (PI(3)K) and the kinase Akt, which suggested environmental regulation. Hence, regulation of KLF2 and S1P1 provides a switch that dictates whether CD8(+) T cells commit to recirculating or tissue-resident memory populations.
Cadmium is among the critical pollutants easily taken up from contaminated media by plants, which can be exploited in the phytoremediation of Cd-contaminated resources, but is also an obstacle in ...producing food with low Cd content. Crucial variables governing Cd biogeochemistry are complex humates (HA) and chlorides, but the underlying interactions are poorly understood. The aim was to determine the impacts of HA (0–60 mg/L) and NaCl (0–30 mM) on Cd biochemistry in contaminated (2.0 μM Cd) rhizosphere solution and Cd accumulation in various tissues of strawberry (Fragaria x ananassa). The results show that salinity (vs. non-saline NaCl0 control) suppressed vegetative and yield parameters, but increased dry matter and Na, Cl and Cd concentration/accumulation in most of the analysed tissues. The HA application in the NaCl0 treatment decreased tissue Cd content; however, at the highest application rates of NaCl and HA, there were increases in the tissue Cd concentration (by 70 %, 100 % and 120 % in crowns, leaves and fruits, respectively) and accumulation (by 110 %, 126 % and 148 % in roots, fruits and leaves, respectively) in comparison to the control (NaCl0HA0). Tissue Cd concentration/accumulation decreased in the order: roots>crowns>leaves>fruits; the same accumulation pattern was noted for Na and Cl, suggesting that Cd-Cl complexes may represent a major form of Cd taken up. Chemical speciation calculations revealed that the proportions of various Cd forms varied multi-fold across the treatments; in the control (without NaCl and HA), Cd2+ dominated (86 %), followed by CdHPO4 (6.5 %), CdSO4 (6.2 %) and CdNO3+. In other treatments the proportion of Cd2+ decreased with a corresponding increase of Cd-Cl (from 0.02 % in control to 57 % in Cd + NaCl30 treatment) and Cd-HA (from 0 % in control to 44 % in Cd + HA60 treatment), which was associated with higher Cd phytoaccumulation. The results represent a theoretical basis for phytoremediation studies and for producing low-Cd food in relatively complex matrices (contaminated soils, reused effluents); in the absence of salinity, amelioration with humates has a great potential to mitigate Cd contamination.
Display omitted
•Humic acid (HA) and NaCl reduce a proportion of the most toxic Cd2+ form by multifold.•NaCl increases a proportion of Cl-Cd ionic forms, increasing Cd uptake by strawberry.•In the absence of NaCl, HA increases a proportion of HA-Cd forms, reducing Cd uptake.•Combined application of HA and NaCl enhances Cd mobility and uptake by strawberry.
Granulocytic myeloid-derived suppressor cells (G-MDSCs) promote tumor growth and immunosuppression in multiple myeloma (MM). However, their phenotype is not well established for accurate monitoring ...or clinical translation. We aimed to provide the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program. The preestablished phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry; surprisingly, we found that CD11b+CD14-CD15+CD33+HLADR- cells overlapped with common eosinophils and neutrophils, which were not expanded in MM patients. Therefore, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, and immature, intermediate, and mature neutrophils. In a series of 267 newly diagnosed MM patients (GEM2012MENOS65 trial), only the frequency of mature neutrophils at diagnosis was significantly associated with patient outcome, and a high mature neutrophil/T-cell ratio resulted in inferior progression-free survival (P < .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMA×CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P = .0007). Most interestingly, RNA sequencing of the 3 subsets revealed that G-MDSC-related genes were specifically upregulated in mature neutrophils from MM patients vs controls because of differential chromatin accessibility. Taken together, our results establish a correlation between the clinical significance, immunosuppressive potential, and transcriptional network of well-defined neutrophil subsets, providing for the first time a set of optimal markers (CD11b/CD13/CD16) for accurate monitoring of G-MDSCs in MM.
Fluid shear stress (FSS) from blood flow acting on the endothelium critically regulates vascular morphogenesis, blood pressure, and atherosclerosis 1. FSS applied to endothelial cells (ECs) triggers ...signaling events including opening of ion channels, activation of signaling pathways, and changes in gene expression. Elucidating how ECs sense flow is important for understanding both normal vascular function and disease. EC responses to FSS are mediated in part by a junctional mechanosensory complex consisting of VE-cadherin, PECAM-1, and VEGFR2 2. Previous work suggested that flow increases force on PECAM-1, which initiates signaling 2–4. Deletion of PECAM-1 blocks responses to flow in vitro and flow-dependent vascular remodeling in vivo 2, 5. To understand this process, we developed and validated FRET-based tension sensors for VE-cadherin and PECAM-1 using our previously developed FRET tension biosensor 6. FRET measurements showed that in static culture, VE-cadherin in cell-cell junctions bears significant myosin-dependent tension, whereas there was no detectable tension on VE-cadherin outside of junctions. Onset of shear stress triggered a rapid (<30 s) decrease in tension across VE-cadherin, which paralleled a decrease in total cell-cell junctional tension. Flow triggered a simultaneous increase in tension across junctional PECAM-1, while nonjunctional PECAM-1 was unaffected. Tension on PECAM-1 was mediated by flow-stimulated association with vimentin. These data confirm the prediction that shear increases force on PECAM-1. However, they also argue against the current model of passive transfer of force through the cytoskeleton to the junctions 7, showing instead that flow triggers cytoskeletal remodeling, which alters forces across the junctional receptors.
Display omitted
•VE-cadherin is under myosin-dependent tension•Flow triggers decreased tension on VE-cadherin by reducing overall contractility•Flow triggers increased tension on PECAM-1 through attachment to vimentin•The data suggest that an unidentified upstream mechanosensor initiates signaling
•Mn-doped Cd3As2 crystals were obtained from elemental and binary precursors.•Mn doping promotes structural transition into secondary polymorph modification.•At lower Mn content ternary Cd3−xMnxAs2 ...compound is formed.•Above solubility limit (x~0.13) the MnAs phase was detected.•The formation of CdAs2 phase in Cd3−xMnxAs2 + MnAs composites is suppressed.
Display omitted
We studied the effect of Mn on the structure and properties of Cd3−xMnxAs2 crystals with x = 0–0.24, synthesized by direct fusion of high-purity elements. Obtained X-ray diffraction patters suggest that the incorporation of Mn promotes a structural phase transition from primary α-Cd3As2 (x = 0) phase to the α''– Cd3As2 (x = 0.24) phase, while at intermediate compositions both phases can coexist. In addition, the increase of Mn content results in the decrease of lattice cell parameters, which effectively saturates for x > 0.13. Microstructural, calorimetric and magnetometry studies suggest that at high Mn content (x = 0.24) secondary MnAs phase appears. Using obtained results, we estimated the solubility limit of Mn in Cd3As2 as x~0.13, which corresponds to the formation of ternary Cd3−xMnxAs2 compound where Cd atoms are partially substituted by Mn. Formation of ternary compound was also suggested by the results for Cd3As2 + MnAs composite systems, where we also observed the presence of CdAs2 phase, which is a byproduct of corresponding reaction. Additional studies suggested that the CdAs2 phase formation in composite system can be prevented if one uses the Cd3−xMnxAs2 compound instead of pure Cd3As2 as a matrix material.
Myeloid-derived suppressor cells (MDSCs) have emerged as major regulators of immune responses in cancer and other pathological conditions. In recent years, ample evidence supports key contributions ...of MDSC to tumour progression through both immune-mediated mechanisms and those not directly associated with immune suppression. MDSC are the subject of intensive research with >500 papers published in 2015 alone. However, the phenotypic, morphological and functional heterogeneity of these cells generates confusion in investigation and analysis of their roles in inflammatory responses. The purpose of this communication is to suggest characterization standards in the burgeoning field of MDSC research.
Soil Cd pollution resulting from human activities has become a serious food safety concern. This study was to investigate the impacts of eight soil amendments including a humic acid material (XZ), ...three organic-inorganic combined materials (FY, PX and PLY) and four inorganic materials (FS, LIME, PLL and PL) on soil Cd availability, enzyme activity, and the uptake by vegetables under incubation, greenhouse and field conditions. Results showed that soil exchangeable Cd (EX-Cd) concentrations under four amendments (FY, XZ, PX, FS) significantly decreased by 12.10–13.59% after 20d treatments, and both PX and PLY resulted in reduced soil EX-Cd fraction while increased fractions of Fe-Mn oxides (OX-Cd), organic matter (OM-Cd) and residual (Res-Cd) in the Cd-contaminated purple soil. PX significantly reduced soil EX-Cd and carbonate-bound (CB-Cd) fractions by 4.4% and 11.4%, and decreased vegetable Cd uptake by 38.8% and 49.1% in greenhouse and field experiments, respectively. Moreover, PX elevated the activities of soil catalase, urease and saccharase by 15.7%, 53.6% and 48.2% in pot soil, which were ~4, ~5 and ~14 times higher those in field soil, respectively. This research demonstrated that PX could be an effective soil amendment to reduce the Cd health and ecological riskthe 1s in the Cd-contaminated purple soil.
Display omitted
•Eight inorganic or organic amendments were firstly applied in purple soil.•Three experiments of the incubation, greenhouse and field were used simultaneously.•Organic-inorganic combined preparations had stable and lasting effects.•Optimum amendment was selected on Cd-contaminated purple soil in southwest China.
Tissue-resident memory T cells (T(RM) cells) provide superior protection against infection in extralymphoid tissues. Here we found that CD103(+)CD8(+) T(RM) cells developed in the skin from ...epithelium-infiltrating precursor cells that lacked expression of the effector-cell marker KLRG1. A combination of entry into the epithelium plus local signaling by interleukin 15 (IL-15) and transforming growth factor-β (TGF-β) was required for the formation of these long-lived memory cells. Notably, differentiation into T(RM) cells resulted in the progressive acquisition of a unique transcriptional profile that differed from that of circulating memory cells and other types of T cells that permanently reside in skin epithelium. We provide a comprehensive molecular framework for the local differentiation of a distinct peripheral population of memory cells that forms a first-line immunological defense system in barrier tissues.
PDF
