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.

Climate warming shifts the time interval between flowering and leaf unfolding depending on the warming period.

The timing of flowering (FL) and leaf unfolding (LU) determine plants' reproduction and vegetative growth. Global warming has substantially advanced FL and LU of temperate and boreal plants, but their responses to warming differ, which may influence the time interval between FL and LU (∆LU-FL), thereby impacting plant fitness and intraspecific physiological processes. Based on twigs collected from two flowering-first tree species, Populus tomentosa and Amygdalus triloba, we conducted a manipulative experiment to investigate the effects of winter chilling, spring warming and photoperiod on the ∆LU-FL. We found that photoperiod did not affect the ∆LU-FL of Amygdalus triloba, but shortened ∆LU-FL by 5.1 d of Populus tomentosa. Interestingly, spring warming and winter chilling oppositely affected the ∆LU-FL of both species. Specifically, low chilling accumulation extended the ∆LU-FL by 3.8 and 9.4 d for Populus tomentosa and Amygdalus triloba, but spring warming shortened the ∆LU-FL by 4.1 and 0.2 d °C-1. Our results indicate that climate warming will decrease or increase the ∆LU-FL depending on the warming periods, i.e., spring or winter. The shifted time interval between flowering and leaf unfolding may have ecological effects including affecting pollen transfer efficiency and alter the structure and functioning of terrestrial ecosystem.

[Study on mechanical properties of nitinol iliac vein stent and animal test under different release scales].

The mechanical properties of nitinol iliac vein stent (NIVS) have been studied by many scholars at home and abroad, but the study on the mechanical properties of iliac vein stent under different release scales has not been reported yet. Based on the finite element analysis method, the mechanical properties of three self-developed NIVS were studied to reveal the influence of stent diameters (12, 14, 16 mm) and different release scales (80%, 90%) on its strength, fatigue life and vein wall biomechanical properties. With an increases in the release scales, the equivalent elastic strain, fatigue strength safety factors, and vessel wall equivalent stress exhibited a downward trend, while the most stressed cross-section coincided with the arc of stent-connecting rods. Through 30, 60 and 90 days' animal test, a narrowed vascular model was established in the iliac veins of 12 pigs, and the developed iliac vein stents were implanted to comprehensively evaluate the safety and effectiveness of the stent, and at the same time the mechanical properties of stents were verified to provide important reference for the type inspection and clinical trials of follow-up products.