Apoptotic cells induce CD103 expression and immunoregulatory function in myeloid dendritic cell precursors through integrin αv and TGF-β activation

International audienceIn the mammalian gut CD103+ve myeloid DCs are known to suppress inflammation threatened by luminal bacteria, but stimuli driving DC precursor maturation towards this beneficial phenotype are incompletely understood. We isolated CD11+ve DCs from mesenteric lymph nodes (MLNs) of healthy mice; CD103+ve DCs were 8-24 fold more likely than CD103-ve DCs to exhibit extensive of prior phagocytosis of apoptotic intestinal epithelial cells. However, CD103+ve and CD103-ve MLN DCs exhibited similar ex vivo capacity to ingest apoptotic cells, indicating that apoptotic cells might drive immature DC maturation towards the CD103+ve phenotype. When cultured with apoptotic cells, myeloid DC precursors isolated from murine bone marrow and characterised as lineage-ve CD103-ve, displayed enhanced expression of CD103 and β8 integrin and acquired increased capacity to induce T regulatory lymphocytes (Tregs) after 7d in vitro. However, DC precursors isolated from αv-tie2 mice lacking αv integrins in the myeloid line exhibited reduced binding of apoptotic cells and complete deficiency in the capacity of apoptotic cells and/or latent TGF-β1 to enhance CD103 expression in culture, whereas active TGF-β1 increased DC precursor CD103 expression irrespective of αv expression. Fluorescence microscopy revealed clustering of αv integrin chains and latent TGF-β1 at points of contact between DC precursors and apoptotic cells. We conclude that myeloid DC precursors can deploy αv integrin to orchestrate binding of apoptotic cells, activation of latent TGF-β1 and acquisition of the immunoregulatory CD103+ve β8+ve DC phenotype. This implies that a hitherto unrecognised consequence of apoptotic cell interaction with myeloid phagocytes is programming that prevents inflammation

H19 Functions as a Competing Endogenous RNA to Regulate EMT by Sponging miR-130a-3p in Glioma

Background/Aims: Glioma is one of the most devasting tumors and confers dismal prognosis. Long noncoding RNAs(lncRNAs) have emerged as important regulators in various tumors including glioma. A classic lncRNA-H19, which is found to be highly expressed in human glioma tissues and cell lines, and is associated with tumor progression thus predicating clinical outcomes in glioma patients. However, the overall biological functions and their mechanism of H19 in glioma are not fully understood. Methods: Firstly, we analyzed H19 alterations in different grades of glioma tissues through an analysis of 5 sequencing datasets and qRT-PCR was performed to confirm the results. Next, we evaluated the effect of H19 on glioma cells migration, invasion and EMT process. Luciferase assays and RIP assays were employed to figure out the correlation of H19 and SOX4. Results: H19 was overexpressed in glioma tissues. Down-regulation of H19 led to the inhibition of migration, invasion and EMT process with a reduction in N-cadherin and Vimentin. H19 and SOX4 are both direct target of miR-130a-3p. H19 could compete with SOX4 via sponging miR-130a-3p. Conclusion: Taken together, these results provide a possible function of H19 as an oncogene in glioma tissues and provide a potential new therapeutic strategy for human glioma

Exposure to the antimicrobial peptide LL-37 produces dendritic cells optimized for immunotherapy

Immunization of patients with autologous, ex vivo matured dendritic cell (DC) preparations, in order to prime antitumor T-cell responses, is the focus of intense research. Despite progress and approval of clinical approaches, significant enhancement of these personalized immunotherapies is urgently needed to improve efficacy. We show that immunotherapeutic murine and human DC, generated in the presence of the antimicrobial host defense peptide LL-37, have dramatically enhanced expansion and differentiation of cells with key features of the critical CD103 + /CD141 + DC subsets, including enhanced cross-presentation and co-stimulatory capacity, and upregulation of CCR7 with improved migratory capacity. These LL-37-DC enhanced proliferation, activation and cytokine production by CD8 + (but not CD4 + ) T cells in vitro and in vivo. Critically, tumor antigen-presenting LL-37-DC increased migration of primed, activated CD8 + T cells into established squamous cell carcinomas in mice, and resulted in tumor regression. This advance therefore has the potential to dramatically enhance DC immunotherapy protocols

Ground Calibration Result of the Lobster Eye Imager for Astronomy

We report on results of the on-ground X-ray calibration of the Lobster Eye Imager for Astronomy (LEIA), an experimental space wide-field (18.6*18.6 square degrees) X-ray telescope built from novel lobster eye mirco-pore optics. LEIA was successfully launched on July 27, 2022 onboard the SATech-01 satellite. To achieve full characterisation of its performance before launch, a series of tests and calibrations have been carried out at different levels of devices, assemblies and the complete module. In this paper, we present the results of the end-to-end calibration campaign of the complete module carried out at the 100-m X-ray Test Facility at IHEP. The PSF, effective area and energy response of the detectors were measured in a wide range of incident directions at several X-ray line energies. The distributions of the PSF and effective areas are roughly uniform across the FoV, in large agreement with the prediction of lobster-eye optics. The mild variations and deviations from the prediction of idealized lobster-eye optics can be understood to be caused by the imperfect shapes and alignment of the micro-pores as well as the obscuration by the supporting frames, which can be well reproduced by MC simulations. The spatial resolution of LEIA defined by the FWHM of the focal spot ranges from 4-8 arcmin with a median of 5.7. The measured effective areas are in range of 2-3 $cm^2$ at ~1.25 keV across the entire FoV, and its dependence on photon energy is in large agreement with simulations. The gains of the CMOS sensors are in range of 6.5-6.9 eV/DN, and the energy resolutions in the range of ~120-140 eV at 1.25 keV and ~170-190 eV at 4.5 keV. These results have been ingested into the calibration database and applied to the analysis of the scientific data acquired by LEIA. This work paves the way for the calibration of the Wide-field X-Ray Telescope modules of the Einstein Probe mission.Comment: 24 pages, 13 figures. Submitted to Experimental Astronom

Surface functionalization of vertical graphene significantly enhances the energy storage capability for symmetric supercapacitors

Vertical graphene (VG) sheets, which consist of few-layer graphene vertically aligned on the substrate with three dimensionally interconnected porous network, make them become one of the most promising energy storage electrodes, especially for SCs. Nevertheless, the intrinsic hydrophobic nature of pristine VG sheets severely limited its application in aqueous SCs. Here, electrochemical oxidation strategy is adopted to increase the hydrophilicity of VG sheets by introducing oxygen functional groups so that the aqueous electrolyte can fully be in contact with the VG sheets to improve charge storage performance. Our work demonstrated that the introduction of oxygen functional groups not only greatly improved the hydrophilicity but also generated a pseudo capacitance to increase the specific capacitance. The resulting capacitance of electrochemically oxidized VG for 7 min (denoted as EOVG-7) exhibited three orders of magnitude higher (1605 mF/cm²) compared to pristine VG sheets. Through assembled two EOVG-7 electrodes, a symmetric supercapacitor demonstrated high specific capacitance of 307.5 mF/cm², high energy density of 138.3 μWh/cm2 as well as excellent cyclic stability (84% capacitance retention after 10000 cycles). This strategy provides a promising way for designing and engineering carbon-based aqueous supercapacitors with high performance

Differential roles for the oxygen sensing enzymes PHD1 and PHD3 in the regulation of neutrophil metabolism and function

Background Neutrophils are essential in the early innate immune response to pathogens. Harnessing their antimicrobial powers, without driving excessive and damaging inflammatory responses, represents an attractive therapeutic possibility. The neutrophil population is increasingly recognised to be more diverse and malleable than was previously appreciated. Hypoxic signalling pathways are known to regulate important neutrophil behaviours and, as such, are potential therapeutic targets for regulating neutrophil antimicrobial and inflammatory responses. Methods We used a combination of in vivo and ex vivo models, utilising neutrophil and myeloid specific PHD1 or PHD3 deficient mouse lines to investigate the roles of oxygen sensing prolyl hydroxylase enzymes in the regulation of neutrophilic inflammation and immunity. Mass spectrometry and Seahorse metabolic flux assays were used to analyse the role of metabolic shifts in driving the downstream phenotypes. Results We found that PHD1 deficiency drives alterations in neutrophil metabolism and recruitment, in an oxygen dependent fashion. Despite this, PHD1 deficiency did not significantly alter ex vivo neutrophil phenotypes or in vivo outcomes in mouse models of inflammation. Conversely, PHD3 deficiency was found to enhance neutrophil antibacterial properties without excessive inflammatory responses. This was not linked to changes in the abundance of core metabolites but was associated with increased oxygen consumption and increased mitochondrial reactive oxygen species (mROS) production. Conclusions PHD3 deficiency drives a favourable neutrophil phenotype in infection and, as such, is an important potential therapeutic target