LPS priming-induced immune tolerance mitigates LPS-stimulated microglial activation and social avoidance behaviors in mice.

In this study, we investigated the regulatory mechanisms underlying the effects of LPS tolerance on the inflammatory homeostasis of immune cells. LPS priming-induced immune tolerance downregulated cyclooxygenase-2, and lowered the production of prostaglandin-E2 in microglial cells. In addition, LPS tolerance downregulated the expression of suppressor of cytokine signaling 3, and inducible nitric oxide synthase/nitric oxide; suppressed the LPS-mediated induction of tumor necrosis factor-α, interleukin (IL)-6, and IL-1; and reduced reactive oxygen species production in microglial cells. LPS stimulation increased the levels of the adaptive response-related proteins heme oxygenase-1 and superoxide dismutase 2, and the levels of heme oxygenase-1 (HO-1) enhanced after LPS priming. Systemic administration of low-dose LPS (0.5 mg/kg) to mice for 4 consecutive days attenuated high-dose LPS (5 mg/kg)-induced inflammatory response, microglial activation, and proinflammatory cytokine expression. Moreover, repeated exposure to low-dose LPS suppressed the recruitment of peripheral monocytes or macrophages to brain regions and downregulated the expression of proinflammatory cytokines. Notably, LPS-induced social avoidance behaviors in mice were mitigated by immune tolerance. In conclusion, immune tolerance may reduce proinflammatory cytokine expression and reactive oxygen species production. Our findings provide insights into the effects of endotoxin tolerance on innate immune cells and social behaviors.

The abrogated role of premedication in the prevention of transfusion-associated adverse reactions in outpatients receiving leukocyte-reduced blood components.

BACKGROUND AND OBJECTIVES: Although it remains controversial, premedication before transfusion is a common clinical practice to prevent transfusion-associated adverse reactions (TAARs) in Taiwan. Thus, we aimed to investigate whether premedication prevented outpatients from developing TAARs and whether an educational programme could improve the understanding of physicians related to the unnecessary use of premedication, and this could elicit changes in their prescribing activities without affecting the occurrence of TAARs. MATERIALS AND METHODS: Clinical data from outpatients receiving transfusion therapy, including predisposing diseases, histories of transfusion and TAARs, premedication and the occurrence of TAARs in the period April 2017 to October 2018, were retrospectively obtained. The evidence-based transfusion programme implemented to educate physicians was started in January 2018. RESULTS: A total of 5018 blood units were transfused to 803 outpatients, with 2493 transfusion events reported in the study interval. The most frequently transfused component was leukocyte-reduced packed red cells (n = 4338), followed by leukocyte-reduced apheresis platelets (n = 540) and other blood components. The overall premedication rate significantly decreased from 92.4% to 76.7% after the educational programme (p < 0.001). There was no remarkable change in the occurrence of TAARs per patient event between the periods before and after the educational programme (1.11% vs. 1.14%, p = 0.964). Besides, it was shown that the occurrence of TAARs was associated with the history of TAARs and inversely related to multiple transfusions, but not premedication. CONCLUSION: Decreased premedication was not associated with increased incidence of TAARs in outpatients; these findings provide important evidence to support the need to revise clinical practices in the era of leukocyte-reduced blood products.

Paliperidone Inhibits Glioblastoma Growth in Mouse Brain Tumor Model and Reduces PD-L1 Expression.

A previous study from our group reported that monocyte adhesion to glioblastoma (GBM) promoted tumor growth and invasion activity and increased tumor-associated macrophages (TAMs) proliferation and inflammatory mediator secretion as well. The present study showed that prescribed psychotropic medicine paliperidone reduced GBM growth and immune checkpoint protein programmed death ligand (PD-L)1 expression and increased survival in an intracranial xenograft mouse model. An analysis of the database of patients with glioma showed that the levels of PD-L1 and dopamine receptor D (DRD)2 were higher in the GBM group than in the low grade astrocytoma and non-tumor groups. In addition, GFP expressing GBM (GBM-GFP) cells co-cultured with monocytes-differentiated macrophage enhanced PD-L1 expression in GBM cells. The enhancement of PD-L1 in GBM was antagonized by paliperidone and risperidone as well as DRD2 selective inhibitor L741426. The expression of CD206 (M2 phenotype marker) was observed to be markedly increased in bone marrow-derived macrophages (BMDMs) co-cultured with GBM. Importantly, treatment with paliperidone effectively decreased CD206 and also dramatically increased CD80 (M1 phenotype marker) in BMDMs. We have previously established a PD-L1 GBM-GFP cell line that stably expresses PD-L1. Experiments showed that the expressions of CD206 was increased and CD80 was mildly decreased in the BMDMs co-cultured with PD-L1 GBM-GFP cells. On the other hands, knockdown of DRD2 expression in GBM cells dramatically decreased the expression of CD206 but markedly increased CD80 expressions in BMDMs. The present study suggests that DRD2 may be involved in regulating the PD-L1 expression in GBM and the microenvironment of GBM. Our results provide a valuable therapeutic strategy and indicate that treatments combining DRD2 antagonist paliperidone with standard immunotherapy may be beneficial for GBM treatment.

CAIX Regulates GBM Motility and TAM Adhesion and Polarization through EGFR/STAT3 under Hypoxic Conditions.

Carbonic anhydrases (CAs) are acid-base regulatory proteins that modulate a variety of physiological functions. Recent findings have shown that CAIX is particularly upregulated in glioblastoma multiforme (GBM) and is associated with a poor patient outcome and survival rate. An analysis of the GSE4290 dataset of patients with gliomas showed that CAIX was highly expressed in GBM and was negatively associated with prognosis. The expression of CAIX under hypoxic conditions in GBM significantly increased in protein, mRNA, and transcriptional activity. Importantly, CAIX upregulation also regulated GBM motility, monocyte adhesion to GBM, and the polarization of tumor-associated monocytes/macrophages (TAM). Furthermore, the overexpression of CAIX was observed in intracranial GBM cells. Additionally, epidermal growth factor receptor/signal transducer and activator of transcription 3 regulated CAIX expression under hypoxic conditions by affecting the stability of hypoxia-inducible factor 1α. In contrast, the knockdown of CAIX dramatically abrogated the change in GBM motility and monocyte adhesion to GBM under hypoxic conditions. Our results provide a comprehensive understanding of the mechanisms of CAIX in the GBM microenvironment. Hence, novel therapeutic targets of GBM progression are possibly developed.

Monocarboxylate Transporter 4 Regulates Glioblastoma Motility and Monocyte Binding Ability.

Glioblastoma (GBM) is characterized by severe hypoxic and acidic stress in an abnormal microenvironment. Monocarboxylate transporter (MCT)4, a pH-regulating protein, plays an important role in pH homeostasis of the glycolytic metabolic pathways in cancer cells. The present study showed that GBM exposure to hypoxic conditions increased MCT4 expression. We further analyzed the glioma patient database and found that MCT4 was significantly overexpressed in patients with GBM, and the MCT4 levels positively correlated with the clinico-pathological grades of gliomas. We further found that MCT4 knockdown abolished the hypoxia-enhanced of GBM cell motility and monocyte adhesion. However, the overexpression of MCT4 promoted GBM cell migration and monocyte adhesion activity. Our results also revealed that MCT4-regulated GBM cell motility and monocyte adhesion are mediated by activation of the serine/threonine-specific protein kinase (AKT), focal adhesion kinase (FAK), and epidermal growth factor receptor (EGFR) signaling pathways. Moreover, hypoxia mediated the acetylated signal transducer and activator of transcription (STAT)3 expression and regulated the transcriptional activity of hypoxia inducible factor (HIF)-1α in GBM cell lines. In a GBM mouse model, MCT4 was significantly increased in the tumor necrotic tissues. These findings raise the possibility for the development of novel therapeutic strategies targeting MCT4.

The effect of ambient exposure to PM2.5 on the transfusion usage of blood components and adverse transfusion reactions in the haze weather.

BACKGROUND: Accumulating evidence has shown that ambient exposure to PM2.5, especially in the haze weather, increased the risk of various diseases. However, the association of air pollution status with blood transfusion utilization and the prevalence and severity of adverse transfusion reactions remain to be clarified. MATERIALS AND METHODS: The data of monthly transfusion usage of blood components, adverse transfusion reactions, as well as PM2.5 and PM10 levels from 2013 to 2015 were obtained. RESULTS: During the study interval, both PM2.5 and PM10 levels were significantly increased in the haze weather when compared with the non-haze weather. The utilization of total blood components per patient-month in the haze weather was prone to be increased when compared with that in the non-haze weather (13.28 ± 1.66 vs. 12.33 ± 1.30, p = 0.068). The usage of RBC products per patient-month in the haze weather was significantly increased when compared with that in the non-haze weather (4.39 ± 0.39 vs. 4.07 ± 0.30, p = 0.009). There was no obvious difference between the haze and non-haze weathers for the usage of platelet and plasma products per patient-month. Besides, no definite differences of the prevalence and severity of transfusion-associated adverse reaction were observed between the haze and non-haze weathers. CONCLUSION: Our study first indicated that transfusion utilization, particularly the RBC products, was significantly increased in the haze weather when compared with that in the non-haze weather. There was no obvious association of air pollution with the prevalence and severity of adverse transfusion reactions and further research is required.