Different modes of cell death regulate immunity. Whereas necrotic (necroptotic, pyroptotic) cell death triggers inflammation, apoptosis contributes to its resolution. Interleukin-1 (IL-1) family cytokines are key players in this interaction. A number of IL-1 family cytokines are produced by necrotic cells to induce sterile inflammation. However, release of IL-1 family proteins from apoptotic cells to regulate inflammation was not described. Here we show that IL-38, a poorly characterized IL-1 family cytokine, is produced selectively by human apoptotic cells to limit inflammation. Depletion of IL-38 in apoptotic cells provoked enhanced IL-6 and IL-8 levels and AP1 activation in co-cultured human primary macrophages, subsequently inducing Th17 cell expansion at the expense of IL-10-producing T cells. IL-38 was N-terminally processed in apoptotic cells to generate a mature cytokine with distinct properties. Both full-length and truncated IL-38 bound to X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1). However, whereas the IL-38 precursor induced an increase in IL-6 production by human macrophages, truncated IL-38 reduced IL-6 production by attenuating the JNK/AP1 pathway downstream of IL1RAPL1. In conclusion, we identified a mechanism of apoptotic cell-dependent immune regulation requiring IL-38 processing and secretion, which might be relevant in resolution of inflammation, autoimmunity, and cancer.

Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10−8) level: 14q24.2 (rs227425, P-value 3.98 × 10−13, SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10−9, CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n = 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.

Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or gd T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon gd T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress gd T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by gd T cells. Our findings indicate a role for IL-38 in the regulation of gd T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease.

Water availability is an important environmental factor that controls flowering time. Many plants accelerate flowering under drought conditions, a phenomenon called drought escape. Four pathways are involved in controlling flowering time, but which ones participate in drought escape is not yet known. In this study, plants with loss-of-function mutations of GIGANTEA (GI) and CONSTANS (CO) exhibited abnormal drought-escape phenotypes. The peak mRNA levels of GI and FKF1 (Flavin-binding Kelch domain F box protein 1) and the mRNA levels of CO and FT (Flowering locus T) changed under drought stress. The microRNA factor miRNA172E was up-regulated by drought stress, and its up-regulation was dependent on GI, while other miRNA172s were not. Water-loss analyses indicated that gi mutants were more sensitive while miRNA172 over-expressing (miRNA172-OX) plants were less so to drought stress than wild-type plants. Digital gene expression and real-time PCR analyses showed that WRKY44 was down-regulated by GI and miRNA172. The WRKY44 protein could interact with TOE1 (a target of miRNA172) in a yeast two-hybrid system. We proposed that GI–miRNA172–WRKY44 may regulate drought escape and drought tolerance by affecting sugar signaling in Arabidopsis.

Obesity is a major public health problem with strong genetic determination. Multiple genetic variants have been implicated for obesity by conducting genome-wide association (GWA) studies, primarily focused on body mass index (BMI). Fat body mass (FBM) is phenotypically more homogeneous than BMI and is more appropriate for obesity research; however, relatively few studies have been conducted on FBM. Aiming to identify variants associated with obesity, we carried out meta-analyses of seven GWA studies for BMI-related traits including FBM, and followed these analyses by de novo replication. The discovery cohorts consisted of 21 969 individuals from diverse ethnic populations and a total of over 4 million genotyped or imputed SNPs. The de novo replication cohorts consisted of 6663 subjects from two independent samples. To complement individual SNP-based association analyses, we also carried out gene-based GWA analyses in which all variations within a gene were considered jointly. Individual SNP-based association analyses identified a novel locus 1q21 [rs2230061, CTSS (Cathepsin S)] that was associated with FBM after the adjustment of lean body mass (LBM) (P = 3.57 × 10(-8)) at the genome-wide significance level. Gene-based association analyses identified a novel gene NLK (nemo-like kinase) in 17q11 that was significantly associated with FBM adjusted by LBM. In addition, we confirmed three previously reported obesity susceptibility loci: 16q12 [rs62033400, P = 1.97 × 10(-14), FTO (fat mass and obesity associated)], 18q22 [rs6567160, P = 8.09 × 10(-19), MC4R (melanocortin 4 receptor)] and 2p25 [rs939583, P = 1.07 × 10(-7), TMEM18 (transmembrane protein 18)]. We also found that rs6567160 may exert pleiotropic effects to both FBM and LBM. Our results provide additional insights into the molecular genetic basis of obesity and may provide future targets for effective prevention and therapeutic intervention.

Metals are essential components of all living cells, and in many cases cells trigger and utilize dynamic metal movements for signaling purposes. So, it is very critical to develop the biosensors for determination of metal ions in living systems with high selectivity and accuracy. In this work, taking Cu(2+) as a model, an accurate and selective ratiometric electrochemical biosensor was developed. First, the specific molecule, 2,2',2″-(2,2',2″-nitrilotris(ethane-2,1-diyl)-tris((pyridin-2-ylmethyl)azanediyl)triethanethiol (TPAASH), was designed and synthesized for specific recognition of Cu(2+). Meanwhile, electroactive molecule, 6-(ferrocenyl)hexanethiol (FcHT) was coimmobilized with TPAASH at one electrode as inner reference molecule to provide a built-in correction for avoiding the environmental effects. Thus, the developed biosensor demonstrated high accuracy and remarkable selectivity toward Cu(2+) against other metal ions, amino acids, and so on. In addition, the biosensor also showed high sensitivity due to the electrocatalytic activity of the nanostructured gold flowers. As a result, the present ratiometric electrochemical biosensor was successfully applied in detection of Cu(2+) in brain microdialysates of normal rat brain and that followed by global cerebral ischemia.

The mTOR (mechanistic target of rapamycin) inhibitor rapamycin has long been known for its immune suppressive properties, but it has shown limited therapeutic success when given systemically to patients with psoriasis. Recent data have shown that the mTOR pathway is hyperactivated in lesional psoriatic skin, which probably contributes to the disease by interfering with maturation of keratinocytes. This study investigated the effect of topical rapamycin treatment in an imiquimod-induced psoriatic mouse model. The disease was less severe if the mice had received rapamycin treatment. Immunohistological analysis revealed that rapamycin not only prevented the activation of mTOR signalling (P-mTOR and P-S6 levels), but almost normalized the expression of epidermal differentiation markers. In addition, the influx of innate immune cells into the draining lymph nodes was partially reduced by rapamycin treatment. These data emphasize the role of mTOR signalling in the pathogenesis of psoriasis, and support the investigation of topical mTOR inhibition as a novel anti-psoriatic strategy.

It is very essential to disentangle the complicated inter-relationship between pH and Cu in the signal transduction and homeostasis. To this end, reporters that can display distinct signals to pH and Cu are highly valuable. Unfortunately, there is still no report on the development of biosensors that can simultaneously respond to pH and Cu(2+), to the best of our knowledge. In this work, we developed a single fluorescent probe, AuNC@FITC@DEAC (AuNC, gold cluster; FITC, fluorescein isothiocyanate; DEAC, 7-diethylaminocoumarin-3-carboxylic acid), for biosensing of pH, Cu(2+), and pH/Cu(2+) with different ratiometric fluorescent signals. First, 2,2',2″-(2,2',2″-nitrilotris(ethane-2,1-diyl)tris((pyridin-2-yl-methyl)azanediyl))triethanethiol (TPAASH) was designed for specific recognition of Cu(2+), as well as for organic ligand to synthesize fluorescent AuNCs. Then, pH-sensitive molecule, FITC emitting at 518 nm, and inner reference molecule, DEAC with emission peak at 472 nm, were simultaneously conjugated on the surface of AuNCs emitting at 722 nm, thus, constructing a single fluorescent probe, AuNC@FITC@DEAC, to sensing pH, Cu(2+), and pH/Cu(2+) excited by 405 nm light. The developed probe exhibited high selectivity and accuracy for independent determination of pH and Cu(2+) against reactive oxygen species (ROS), other metal ions, amino acids, and even copper-containing proteins. The AuNC-based inorganic-organic probe with good cell-permeability and high biocompatibility was eventually applied in monitoring both pH and Cu(2+) and in understanding the interplaying roles of Cu(2+) and pH in live cells by ratiometric multicolor fluorescent imaging.