Microglial ApoD-induced NLRC4 inflammasome activation promotes Alzheimer's disease progression.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective therapies. It is well known that chronic neuroinflammation plays a critical role in the onset and progression of AD. Well-balanced neuronal-microglial interactions are essential for brain functions. However, determining the role of microglia-the primary immune cells in the brain-in neuroinflammation in AD and the associated molecular basis has been challenging. METHODS: Inflammatory factors in the sera of AD patients were detected and their association with microglia activation was analyzed. The mechanism for microglial inflammation was investigated. IL6 and TNF-α were found to be significantly increased in the AD stage. RESULTS: Our analysis revealed that microglia were extensively activated in AD cerebra, releasing sufficient amounts of cytokines to impair the neural stem cells (NSCs) function. Moreover, the ApoD-induced NLRC4 inflammasome was activated in microglia, which gave rise to the proinflammatory phenotype. Targeting the microglial ApoD promoted NSC self-renewal and inhibited neuron apoptosis. These findings demonstrate the critical role of ApoD in microglial inflammasome activation, and for the first time reveal that microglia-induced inflammation suppresses neuronal proliferation. CONCLUSION: Our studies establish the cellular basis for microglia activation in AD progression and shed light on cellular interactions important for AD treatment.

Preparation and performance study of multichannel PLA artificial nerve conduits.

Compared with single-channel nerve conduits, multichannel artificial nerve conduits are more beneficial for repairing damaged peripheral nerves of long-distance nerve defects. Multichannel nerve conduits can be fabricated by the mold method and the electrospinning method but with disadvantages such as low strength and large differences in batches, while the braiding method can solve this problem. In this study, polylactic acid yarns were used as the braiding yarn, and the number of spindles during braiding was varied to achieve 4, 5, 6, 7 and 8 multichannel artificial nerve conduits. A mathematical model of the number of braiding yarn spindles required to meet certain size specification parameters of the multichannel conduit was established. The cross-sectional morphology and mechanical properties of the conduits were characterized by scanning electron microscopy observation and mechanical testing; the results showed that the multichannel structure was well constructed; the tensile strength of the multichannel conduit was more than 30 times that of the rabbit tibial nerve. The biocompatibility of the conduit was tested; thein vitrocell culture results proved that the braided multichannel nerve conduits were nontoxic to Schwann cells, and the cell adhesion and proliferation were optimal in the 4-channel conduit among the multichannel conduits, which was close to the single-channel conduit.

Comparison of the Effects of Intraperitoneal Injection with Carbon Tetrachloride on Acute Liver Toxicity in Male and Female Kunming Mice.

BACKGROUND Acute chemical liver injury needs to be further explored. The present study aimed to compare the effects of intraperitoneal injection with carbon tetrachloride on acute liver toxicity after 24 h in male and female Kunming mice. MATERIAL AND METHODS In this study, female and male mice were simultaneously divided into 3 different groups. Each group was treated differently, and after 24 h, blood samples were collected to check for changes in the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which were used to assess liver toxicity. Liver samples were used for hematoxylin-eosin staining, and periodic acid Schiff reagent staining was performed to detect the pathological changes of each group. The expression level of biomarker molecules in liver cells was also systematically analyzed. RESULTS Our results showed that, compared with male mice, female mice showed more serious damage: reduced glycogen and higher degree of necrosis, and the levels of heatshock protein 27 (HSP27), heat-shock protein 70 (HSP70), proliferating cell nuclear antigen (PCNA) and B cell lymphoma/lewkmia-2 (Bcl-2) were significantly lower than in the male group (P<0.05 or P<0.01), while the results of Bcl-2-associated X protein (Bax), cysteinyl aspartate specific proteinase 3 (Caspase3), and cytochrome P450 2E1 (CYP2E1) were the opposite (P<0.05 or P<0.01). CONCLUSIONS The findings from this study showed that, compared with male mice, at 24 h after CCl4 toxicity, female mice showed more severe changes of hepatocyte necrosis and PAS-positivity, with significantly reduced expression of HSP27, HSP70, PCNA, and Bcl-2, and significantly increased expression of Bax, caspase-3, and CYP2E1.

Circulating microRNA profile unveils mechanisms of action of acitretin for psoriasis vulgaris.

Psoriasis vulgaris is a common chronic and recurrent inflammatory skin disease. In clinical practice, acitretin is the first-line treatment drug for psoriasis vulgaris. MicroRNAs (miRNAs) play a vital role in the initiation and development of psoriasis vulgaris. However few studies focused on the mechanisms of acitretin in the treatment of psoriasis vulgaris from the perspective of miRNAs. Here, the expression profiles of circulating miRNAs in the plasma of 12 patients with psoriasis vulgaris before and after acitretin treatment were sequenced. Three miRNAs (miR-146a-5p, miR-122-5p and miR-21-5p) were identified using expression pattern analysis, and the levels were significantly decreased after acitretin treatment (P< 0.001). Receiver operating characteristic (ROC) analyses indicated that the three miRNAs have the potential to be utilized as molecular markers to evaluate the therapeutic effect of acitretin, and the values of the area under the curve (AUC) were 0.825, 0.831, and 0.796, respectively. In addition, we predicted target genes of the three miRNAs and performed signaling pathway enrichment analyses. The results demonstrated that the target genes were mainly involved in the MAPK, JAK-STAT, and NF-κB signaling pathways, which were further validated through in vitro experiments. In conclusion, acitretin can suppress miRNA-mediated MAPK, JAK-STAT, and NF-κB signaling pathways by decreasing miRNAs expression, thereby inhibiting the proliferation and inflammatory response of keratinocytes.

Cancer immunotherapy based on blocking immune suppression mediated by an immune modulator LAIR-1.

The leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is an inhibitory receptor expressed on the majority of peripheral blood mononuclear cells and is important for the regulation of immune responses. The binding of LAIR-1 to its ligands results in the loss of immune function in the tumor microenvironment (TME) and a reduction in T cell function and immune responses of antigen-presenting cells. Using bioinformatics analysis, we showed that LAIR-1 is broadly upregulated in multiple types of cancer. By designing a LAIR-2-Fc recombinant protein to block the binding of LAIR-1 to its ligand collagen, we observed augmented cytotoxic T cell infiltration and function resulting in antitumor immune responses that eliminated cancer cells. Besides, LAIR-2-Fc fusion protein potentiated the antitumor effect of PD-1/L1 checkpoint blockade therapy. Collectively, our results support the targeting of LAIR-1 for potential immunotherapeutic applications.

CD47/SIRPα blocking enhances CD19/CD3-bispecific T cell engager antibody-mediated lysis of B cell malignancies.

T cell immunotherapies are promising options in leukemia, among which the CD19/CD3-bispecific T cell engager antibody blinatumomab (MT103) has shown high response rates at very low doses in patients with lymphoma. However, the high CD47 expression in human lymphoma cells has limited the curative effects of blinatumomab other antibodies. Here we report the combined use of blinatumomab with a CD47-blocking antibody. CD47 antibodies preferentially enabled phagocytosis of non-Hodgkin lymphoma cells by both human and murine macrophages. Treatment of human non-Hodgkin lymphoma cell-engrafted mice with CD47 antibody and blinatumomab separately inhibited lymphoma partially, while combination treatment led to persistent control of lymphoma. These antibodies enhanced the therapeutic efficacy through mechanisms combining both innate and adaptive immune responses by induction of phagocytosis and T cell cytotoxicity. The combination strategy in this study might be applicable to many other cancers.