Neurons upregulate PD-L1 via IFN/STAT1/IRF1 to alleviate damage by CD8+ T cells in cerebral malaria.

BACKGROUND: Cerebral malaria (CM) is the most lethal complication of malaria, and survivors usually endure neurological sequelae. Notably, the cytotoxic effect of infiltrating Plasmodium-activated CD8+ T cells on cerebral microvasculature endothelial cells is a prominent feature of the experimental CM (ECM) model with blood-brain barrier disruption. However, the damage effect of CD8+ T cells infiltrating the brain parenchyma on neurons remains unclear. Based on the immunosuppressive effect of the PD-1/PD-L1 pathway on T cells, our previous study demonstrated that the systemic upregulation of PD-L1 to inhibit CD8+ T cell function could effectively alleviate the symptoms of ECM mice. However, it has not been reported whether neurons can suppress the pathogenic effect of CD8+ T cells through the PD-1/PD-L1 negative immunomodulatory pathway. As the important inflammatory factor of CM, interferons can induce the expression of PD-L1 via different molecular mechanisms according to the neuro-immune microenvironment. Therefore, this study aimed to investigate the direct interaction between CD8+ T cells and neurons, as well as the mechanism of neurons to alleviate the pathogenic effect of CD8+ T cells through up-regulating PD-L1 induced by IFNs. METHODS: Using the ECM model of C57BL/6J mice infected with Plasmodium berghei ANKA (PbA), morphological observations were conducted in vivo by electron microscope and IF staining. The interaction between the ECM CD8+ T cells (immune magnetic bead sorting from spleen of ECM mice) and primary cultured cortical neurons in vitro was observed by IF staining and time-lapse photography. RNA-seq was performed to analyze the signaling pathway of PD-L1 upregulation in neurons induced by IFNß or IFNγ, and verified through q-PCR, WB, IF staining, and flow cytometry both in vitro and in vivo using IFNAR or IFNGR gene knockout mice. The protective effect of adenovirus-mediated PD-L1 IgGFc fusion protein expression was verified in ECM mice with brain stereotaxic injection in vivo and in primary cultured neurons via viral infection in vitro. RESULTS: In vivo, ECM mice showed infiltration of activated CD8+ T cells and neuronal injury in the brain parenchyma. In vitro, ECM CD8+ T cells were in direct contact with neurons and induced axonal damage, as an active behavior. The PD-L1 protein level was elevated in neurons of ECM mice and in primary cultured neurons induced by IFNß, IFNγ, or ECM CD8+ T cells in vitro. Furthermore, the IFNß or IFNγ induced neuronal expression of PD-L1 was mediated by increasing STAT1/IRF1 pathway via IFN receptors. The increase of PD-L1 expression in neurons during PbA infection was weakened after deleting the IFNAR or IFNGR. Increased PD-L1 expression by adenovirus partially protected neurons from CD8+ T cell-mediated damage both in vitro and in vivo. CONCLUSION: Our study demonstrates that both type I and type II IFNs can induce neurons to upregulate PD-L1 via the STAT1/IRF1 pathway mediated by IFN receptors to protect against activated CD8+ T cell-mediated damage, providing a targeted pathway to alleviate neuroinflammation during ECM.

CD8+ T cell infiltration and proliferation in the brainstem during experimental cerebral malaria.

INTRODUCTION: Cerebral malaria (CM) is a lethal neuroinflammatory disease caused by Plasmodium infection. Immune cells and brain parenchyma cells contribute to the pathogenesis of CM. However, a systematic examination of the changes that occur in the brain parenchyma region during CM at the single-cell resolution is still poorly studied. AIMS: To explore cell composition and CD8+ T cell infiltration, single-cell RNA sequencing (scRNA-seq) was performed on the brainstems of healthy and experimental cerebral malaria (ECM) mice. Then CD8+ T cell infiltration was confirmed by flow cytometry and immunofluorescence assays. Subsequently, the characteristics of the brain-infiltrated CD8+ T cells were analyzed. Finally, the interactions between parenchyma cells and brain-infiltrated CD8+ T cells were studied with an astrocytes-CD8+ T cell cocultured model. RESULTS: The brainstem is the most severely damaged site during ECM. ScRNA-seq revealed a large number of CD8+ T cells infiltrating into the brainstem in ECM mice. Brain-infiltrated CD8+ T cells were highly activated according to scRNA-seq, immunofluorescence, and flow cytometry assays. Further analysis found a subset of ki-67+ CD8+ T cells that have a higher transcriptional level of genes related to T cell function, activation, and proliferation, suggesting that they were exposed to specific antigens presented by brain parenchyma cells. Brain-infiltrated CD8+ T cells were the only prominent source of IFN-γ in this single-cell analysis. Astrocytes, which have a high interferon response, act as cross-presenting cells to recruit and re-activate brain-infiltrated CD8+ T cells. We also found that brain-infiltrated CD8+ T cells were highly expressed immune checkpoint molecule PD-1, while parenchyma cells showed up-regulation of PD-L1 after infection. CONCLUSIONS: These findings reveal a novel interaction between brain-infiltrated CD8+ T cells and parenchyma cells in the ECM brainstem, suggesting that the PD-1/PD-L1 signal pathway is a promising adjunctive therapeutic strategy for ECM targeting over-activated CD8+ T cells.

Dynamic Spectral Modulation on Meta-Waveguides Utilizing Liquid Crystal.

The integration of metasurfaces and optical waveguides is gradually attracting the attention of researchers because it allows for more efficient manipulation and guidance of light. However, most of the existing studies focus on passive devices, which lack dynamic modulation. This work utilizes the meta-waveguides with liquid crystal(LC) to modulate the on-chip spectrum, which is the first experimentally verified, to the authors' knowledge. By applying a voltage, the refractive index of the liquid crystal surrounding the meta-waveguides can be tuned, resulting in a blue shift of the spectrum. The simulation shows that the 18.4 dB switching ratio can be achieved at 1550 nm. The meta-waveguides are prepared using electron beam lithography (EBL), and the improved transmittance of the spectrum in the short wavelength is experimentally verified, which is consistent with the simulation trend. At 1551.64 nm wavelength, the device achieves a switching ratio of ≈16 dB with an active area of 8 µm × 0.4 µm. Based on this device, an optoelectronic computing architecture for the Hadamard matrix product and a novel wavelength selection switch are proposed. This work offers a promising avenue for on-chip dynamic modulation in integrated photonics, which has the advantage of a compact active area, fast response time, and low energy consumption compared to conventional thermal-light modulation.

Improved photoacoustic images via wavefront shaping modulation based on the scattering structure: retraction.

The referenced article [Opt. Express30, 36489 (2022)10.1364/OE.470330] has been retracted by the authors.

Ultracompact Polarization Splitter-Rotator Based on Shallowly Etched Subwavelength Gratings and Anisotropic Metasurfaces.

Polarization splitter-rotators (PSRs) are an essential component in on-chip polarization-sensitive and polarization-division multiplexing systems. In this work, we propose an ultracompact and high-performance silicon-based polarization splitter-rotator utilizing anisotropic metasurfaces, which is the first to combine the two, to our knowledge. The tilted periodic metasurface structure has different modulation effects on different polarized light fields, such as the transverse-electric (TE) mode and the transverse-magnetic (TM) mode, which are beneficial for designing polarization management devices. According to the results, the entire length of the silicon PSR was ~13.5 µm. The TE-to-TM conversion loss and polarization conversion ratio ere -0.154 dB and 96.5% at 1.55 µm, respectively. In the meanwhile, the cross talk and reflection loss were -27.0 dB and -37.3 dB, when the fundamental TE mode was input. The insertion loss and cross talk were -0.19 dB and -25.01 dB at the central wavelength when the fundamental TM mode was input. In addition, the bandwidth reached up to ~112 nm with polarization conversion loss and insertion loss higher than -0.46 dB and -0.36 dB. The simulations also show that the designed devices had good fabrication tolerance.

Infrared metasurface absorber based on silicon-based CMOS process.

Metasurface with metal-insulator-metal (MIM) structure has absorption properties for incident light at specific wavelengths. In this paper, we propose an infrared metasurface absorber based on silicon-based complementary metal oxide semiconductor (CMOS) process. By adding the prepared infrared metasurface absorber to the liquid crystal on silicon (LCoS) chip, it is used as the absorbing layer of LCoS configured between the pixel unit and the CMOS driver circuit. The effect of zero-order light caused by the gap between pixels in LCoS spatial light modulator (LCoS-SLM) on the light modulation function of the device is effectively reduced. Experiments show that the LCoS-SLM with infrared metasurface absorption structure can eliminate the zero-order light interference between the pixel gaps to a great extent and improve the modulation efficiency of the device. The proposed LCoS-SLM integrating infrared metasurface absorber structure based on silicon-based CMOS process has the advantages of low-cost and high modulation efficiency, which has high application value in the fields of holographic display, optical computing and optical communication.

Improved photoacoustic images via wavefront shaping modulation based on the scattering structure.

Multispectral optoacoustic tomography (MSOT) has become the dominant technical solution for photoacoustic imaging (PAI). However, the laser source of fiber output in the current MSOT method is typically a TEM00 Gaussian beam, which is prone to artifacts and incomplete due to the uneven distribution of the irradiated light intensity. Here, we propose a novel method to improve the quality of photoacoustic image reconstruction by modulating the wavefront shaping of the incident laser beam based on the designed scattering structure. In the experiment, we add the designed scattering structure to the current hemispherical photoacoustic transducer array device. Through experiments and simulations, we investigate and compare the effects of different scattering structures on laser intensity modulation. The results show that an ED1-C20 diffusion structure with a scattering angle of 20 degrees has the most effective modulation of the beam intensity distribution. And we choose gold nanoparticles of 50-100 nanometers (nm) diameters and index finger capillary vessels respectively as the medium of PAI. We obtain the highest ratio of PAI area increases of gold nanoparticles and index finger to devices compare without scattering structure is 29.69% and 634.94%, respectively. Experimental results demonstrate that our method is significantly higher quality than traditional methods, which has great potential for theoretical application in medical PAI.

Ferroptosis participates in neuron damage in experimental cerebral malaria and is partially induced by activated CD8+ T cells.

Cerebral malaria is the most serious complication of malaria infection, with 26% of surviving children having neurological sequelae, which may be caused by neuron damage, but the mechanism is not clear. Ferroptosis has been reported to play an important role in neuron damage in several nervous system diseases. However, the occurrence of ferroptosis in experimental cerebral malaria (ECM) pathogenesis is still unknown. In this study, we firstly detected increased levels of malondialdehyde (MDA) and iron, which are indicators of ferroptosis, in the cerebrum of ECM mice. Some important regulators of ferroptosis, including upregulated expression of transferrin receptor 1 (TfR1) and acyl-CoA synthetase long-chain family member 4 (ACSL4), and downregulation of glutathione peroxidase 4 (GPX4) levels, were also confirmed in ECM mice. Consistently, neuron damage, which was detected in the cerebrum of ECM mice, was positively correlated with reduced GPX4 expression and furtherly rescued by administration of the ferroptosis inhibitor ferrostatin-1 (Fer-1). In addition, primary neurons were damaged by activated CD8+ T cells, an effect that was also partially rescued by Fer-1 on amyloid precursor protein expression and mitochondrial membrane potential levels in vitro. Activated CD8+ T cells were also shown to infiltrate the cerebrum of ECM mice and upregulate TfR1 expression in primary neurons, which may be an important event for inducing ferroptosis in ECM. Altogether, we show that ferroptosis contributes to neuron damage in ECM pathogenesis, and activated CD8+ T cells may be important inducers of neuronal ferroptosis. Hence, targeting ferroptosis may be a promising adjuvant therapeutic strategy for neurological sequelae in patients with cerebral malaria.

Large-area all-dielectric metasurface fabricated by an anodized aluminum oxide template.

Transmissive metasurfaces formed by high-index dielectric materials have received great attention due to its potential in holograms, deflectors, beam converters, and flat lenses. However, a key challenge of all-dielectric metasurfaces is the limited scale and high cost in fabrication, such as electron beam lithography (EBL) and focused ion beam (FIB) lithography. In this paper, for the first time to our knowledge, an anodized aluminum oxide (AAO) template is combined with titanium dioxide (TiO2) metasurface fabrication with advantages of large area (>2cm2) and low cost. Using the ordered anodized aluminum oxide (AAO) as an evaporation mask, a TiO2 nanocylinder array is deposited through the AAO mask onto the SiO2 substrate. Electric and magnetic dipole resonances of TiO2 metasurface appear in the visible spectrum. Furthermore, we demonstrate the interaction of the CsPbBr1.5I1.5 quantum dot (QD) emission with magnetic dipole (MD) resonance of TiO2 metasurface. Our results reveal that the metasurface exhibits remarkable photoluminescence (PL) enhancement of 25%. Up to now, a TiO2 metasurface with 2.25-cm2-large area using AAO template method has never been attempted. Different from the metasurfaces fabricated by FIB and EBL, our method offers great ease for large-area metasurface fabrication, which is convenient for metasurface researchers and avoids costly facilities.

Super-Resolution Imaging with Direct Laser Writing-Printed Microstructures.

Dielectric microstructures coupled with a conventional optical microscope have been proven to be a successful way to achieve super-resolution imaging. However, a limitation of such super-resolution imaging is the microstructure fabrication ability, which generally provides natural structures (such as spherical, hemispherical, superhemispherical microlenses, and so on). Meanwhile, the influences of microstructures with complex shapes on the super-resolved imaging still remain unknown. In this paper, direct laser writing (DLW) lithography is used to produce a series of complex microstructures, which are capable of achieving super-resolution imaging in the optical far-field region. Cylinder, truncated cone, hemisphere, and protruding hemisphere microstructures are successfully fabricated by this 3D printing technology, allowing us to resolve features as small as 100 nm under classical microscopy. Moreover, different microstructures lead to different photonic nanojet (PNJ) illuminations and collection efficiencies, resulting in a critical role in super-resolved imaging. The microstructures with spherical surfaces can easily collect the light scattered by the object and convert the high-spatial-frequency evanescent waves into propagating waves.