Tumor-associated macrophages affect the treatment of lung cancer.

As one of the most common malignant tumors in the world, lung cancer has limited benefits for patients despite its diverse treatment methods due to factors such as personalized medicine targeting histological type, immune checkpoint expression, and driver gene mutations. The high mortality rate of lung cancer is partly due to the immune-suppressive which limits the effectiveness of anti-cancer drugs and induces tumor cell resistance. The currently widely recognized TAM phenotypes include the anti-tumor M1 and pro-tumor M2 phenotypes. M2 macrophages promote the formation of an immune-suppressive microenvironment and hinder immune cell infiltration, thereby inhibiting activation of the anti-tumor immune system and aiding tumor cells in resisting treatment. Analyzing the relationship between different treatment methods and macrophages in the TME can help us better understand the impact of TAMs on lung cancer and confirm the feasibility of targeted TAM therapy. Targeting TAMs to reduce the M2/M1 ratio and reverse the immune-suppressive microenvironment can improve the clinical efficacy of conventional treatment methods and potentially open up more efficient combination treatment strategies, maximizing the benefit for lung cancer patients.

Feasibility and safety of EGFR-TKI neoadjuvant therapy for EGFR-mutated NSCLC: A meta-analysis.

BACKGROUND: The role of neoadjuvant epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) targeted therapy for EGFR-mutated non-small cell lung cancer (NSCLC) is unclear. Previous studies have shown that EGFR-TKIs have excellent anti-tumor activity. However, almost all studies on neoadjuvant EGFR-TKI treatment for EGFR-mutated NSCLC have been non-randomized controlled trials with small sample sizes and different methods of statistical analysis, which may lead to a lack of valid metrics to assess the feasibility and safety of neoadjuvant EGFR-TKI treatment. This meta-analysis aimed to assess the efficacy and safety of neoadjuvant EGFR-TKI treatment for NSCLC patients with EGFR mutations. METHODS: Relevant studies were systematically searched in PubMed, Embase, and Web of Science databases. Results including objective response rate (ORR), complete resection rate (R0), downstaging rate, pathological complete response (PCR), major pathological response (MPR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were used for further analysis. RESULTS: This meta-analysis ultimately included 11 studies involving 344 patients with EGFR-positive mutations in NSCLC. In terms of tumor response, the pooled ORR was 57% (95% CI: 42%-73%), and in the Osimertinib subgroup, the pooled ORR was 80% (95% CI: 63%-98%). Analysis of studies that reported a downstaging rate showed the pooled downstaging rate of 41% (95% CI: 9%-74%) and the pooled downstaging rate of 74% (95% CI: 22%-100%) in the Osimertinib subgroup. In terms of surgical outcomes, the pooled pCR rate was 3% (95% CI: 0%-7%), the pooled MPR rate was 11% (95% CI: 6%-17%), and the pooled R0 resection rate was 91% (95% CI: 85%-95%). The most common adverse events associated with neoadjuvant therapy were rash and diarrhea. The pooled incidence of any grade of rash was 47.1% (95% CI: 25.4%-69.3%), and the pooled incidence of grade ≥ 3 rash was 0.6% (95% CI: 0.0%-2.5%). The pooled incidence of diarrhea of any grade was 28.8% (95% CI: 14.4%-45.4%), with the pooled incidence of grade ≥ 3 diarrhea of 0.2% (95% CI: 0.0%-1.6%). The pooled incidence of ≥ grade 3 adverse events was significantly lower. CONCLUSIONS: Our meta-analysis confirmed the efficacy and safety of neoadjuvant EGFR-TKIs for the treatment of NSCLC patients with EGFR-positive mutations and that third-generation EGFR-TKIs were superior to first- and second-generation EGFR-TKIs in terms of shrinking tumor volume and lowering tumor stage; however, future large-scale and multicenter randomized controlled trials are needed to confirm this conclusion. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023466731.

Hypoxia-mediated promotion of glucose metabolism in non-small cell lung cancer correlates with activation of the EZH2/FBXL7/PFKFB4 axis.

F-box/LRR-repeat protein 7 (FBXL7) was predicted as a differentially expressed E3 ubiquitin ligase in non-small cell lung cancer (NSCLC), which has been suggested to influence cancer growth and metastasis. In this study, we aimed to decipher the function of FBXL7 in NSCLC and delineate the upstream and downstream mechanisms. FBXL7 expression was verified in NSCLC cell lines and GEPIA-based tissue samples, after which the upstream transcription factor of FBXL7 was bioinformatically identified. The substrate PFKFB4 of the FBXL7 was screened out by tandem affinity purification coupled with mass-spectrometry (TAP/MS). FBXL7 was downregulated in NSCLC cell lines and tissue samples. FBXL7 ubiquitinated and degraded PFKFB4, thus suppressing glucose metabolism and malignant phenotypes of NSCLC cells. Hypoxia-induced HIF-1α upregulation elevated EZH2 and inhibited FBXL7 transcription and reduced its expression, thus promoting PFKFB4 protein stability. By this mechanism, glucose metabolism and the malignant phenotype were enhanced. In addition, knockdown of EZH2 impeded tumor growth through the FBXL7/PFKFB4 axis. In conclusion, our work reveals that the EZH2/FBXL7/PFKFB4 axis plays a regulatory role in glucose metabolism and tumor growth of NSCLC, which is expected to be potential biomarkers for NSCLC.

3D hollow NiCo LDH nanocages anchored on 3D CoO sea urchin-like microspheres: A novel 3D/3D structure for hybrid supercapacitor electrodes.

The research on the structure of advanced electrode materials is significant in the field of supercapacitors. Herein, for the first time, we propose a novel 3D/3D composite structure by a multi-step process, in which 3D hollow NiCo LDH nanocages are immobilized on 3D sea urchin-like CoO microspheres. Results show that the 3D CoO acts as an efficient and stable channel for ion diffusion, while the hollow NiCo LDH provides abundant redox-active sites. The calculated results based on density function theory (DFT) show that the CoO@NiCo LDH heterostructure has an enhanced density of states (DOS) near the Fermi level and strong adsorption capacity for OH-, indicating its excellent electrical conductivity and electrochemical reaction kinetics. As a result, the CoO@NiCo LDH electrode has an areal specific capacity of 4.71C cm-2 at a current density of 3 mA cm-2 (440.19C g-1 at 0.28 A g-1) and can still maintain 88.76 % of the initial capacitance after 5000 cycles. In addition, the assembled hybrid supercapacitor has an energy density of 5.59 mWh cm-3 at 39.54 mW cm-3.

N-Myc transcriptionally activates Skp2 to suppress p27 expression in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is characterized by a high proliferative rate, a strong predilection for early metastasis and poor prognosis. Novel SCLC biomarkers are urgently required to improve current diagnostic and treatment modalities. MYCN encodes the proto-oncogene N-Myc that is overexpressed in SCLC, but its downstream effectors are poorly characterized. Here, we investigated the role of the N-Myc/Skp2/p27 axis during SCLC progression. METHODS: Immunohistochemistry (IHC) and western blotting were performed to evaluate N-Myc/Skp2/p27 expression. SCLC cell apoptosis was investigated through TUNEL staining. Wound healing and transwell assays were performed to detect the migratory and invasive potential of SCLC cells. N-Myc and Skp2 binding was confirmed through luciferase reporter and ChIP assays. Xenograft models were developed to investigate the function of Skp2 during SCLC tumor growth in vivo. RESULTS: N-Myc and Skp2 were overexpressed in SCLC, whilst p27 expression was suppressed. Skp2 facilitated SCLC progression by protecting cells from apoptosis and facilitating cell migration and invasion. N-Myc was found to bind to the promoter region of Skp2 to enhance its expression. Skp2 enhanced tumor growth in vivo through the suppression of p27. Skp2 silencing reversed the pro-oncogenic effects of N-myc in SCLC tumors. CONCLUSION: We show that N-Myc enhances Skp2 to regulate p27 expression during SCLC progression. We therefore highlight the N-Myc/Skp2/p27 axis as a novel diagnostic and much-needed therapeutic target in SCLC.

Heat shock protein 47 promotes cell migration and invasion through AKT signal in non-small cell lung cancer.

Lung cancer is one of the most lethal malignancies, with the highest number of cases and deaths. Non-small cell lung cancer (NSCLC) is the most ordinary type of pathology in lung cancer. Meanwhile, various researchers have reported that heat shock protein 47 (HSP47) plays a vital regulatory role in cancer. However, the role of HSP47 in NSCLC is not clear. Consequently, the current study set out to investigate the role of HSP47 in the pathogenesis of NSCLC. First, we evaluated the expression patterns of HSP47 in NSCLC cell lines related to human normal lung epithelial cells, and HSP47 was found to be highly expressed in NSCLC cell lines. In addition, inhibiting the expression of HSP47 brought about marked repression in cell proliferation, migration and invasion in PC-9 cells. On the contrary, cell proliferation, migration and invasion were all elevated after over-expression of HSP47. Mechanistical experimentation further illustrated that protein kinase B (AKT) signal was repressed after inhibition of HSP47, and the influence of sh-HSP47 on cell proliferation, migration and invasion was countered by epidermal growth factor. Lastly, in-vivo animal models demonstrated that inhibition of HSP47 repressed cell tumorigenesis and AKT signal. Collectively, our findings illustrated that HSP47 was highly expressed in NSCLC cell lines, whereas inhibition of HSP47 repressed cell migration and invasion by diminishing the AKT signal. Inhibition of HSP47 also exhibited strong therapeutic effects on NSCLC in vivo.

Established Beta Amyloid Pathology Is Unaffected by TREM2 Elevation in Reactive Microglia in an Alzheimer's Disease Mouse Model.

Several genetic studies have identified a rare variant of triggering receptor expressed on myeloid cells 2 (TREM2) as a risk factor for Alzheimer's disease (AD). However, findings on the effects of TREM2 on Aß deposition are quite inconsistent in animal studies, requiring further investigation. In this study, we investigated whether elevation of TREM2 mitigates Aß pathology in TgCRND8 mice. We found that peripheral nerve injury resulted in a robust elevation of TREM2 exclusively in reactive microglia in the ipsilateral spinal cord of aged TgCRND8 mice at the age of 20 months. TREM2 expression appeared on day 1 post-injury and the upregulation was maintained for at least 28 days. Compared to the contralateral side, neither amyloid beta plaque load nor soluble Aß40 and Aß42 levels were attenuated upon TREM2 induction. We further showed direct evidence that TREM2 elevation in reactive microglia did not affect amyloid-ß pathology in plaque-bearing TgCRND8 mice by applying anti-TREM2 neutralizing antibody to selectively block TREM2. Our results question the ability of TREM2 to ameliorate established Aß pathology, discouraging future development of disease-modifying pharmacological treatments targeting TREM2 in the late stage of AD.

A meta-analysis of cohort studies: Traumatic brain injury and risk of Alzheimer's Disease.

INTRODUCTION: Recently, some epidemiological studies have reported that cognitive disorders in elderly people is accelerated with traumatic brain injury. But the causal relationship between traumatic brain injury and AD is still an area of controversy. AIMS: Our review was conducted to estimate the relation between traumatic brain injury and risk of AD. METHODS: All longitudinal population-based studies comparing incidence of AD between subjects with and without traumatic brain injury from their inception to September 2020 were searched in The Cochrane Library, PubMed, Medline, Embase, Web of Science without restriction of language. The meta-analysis was conducted using Stata software. RESULTS: A total of 17 studies involving 4289,548 individuals were included. After pooling these 17 studies, subjects with traumatic brain injury had significant higher incidence of AD than those without traumatic brain injury (RR: 1.17, 95% CI: 1.05-1.29). When considering the severity of traumatic brain injury, this elevated risk of AD was still significant comparing subjects with moderate and severe traumatic brain injury and those with no traumatic brain injury (RR: 1.30, 95% CI: 1.01-1.59). CONCLUSION: Traumatic brain injury, especially moderate and severe traumatic brain injury may be associated with increased risk of AD.

Cyclosporin A impairs neurogenesis and cognitive abilities in brain development via the IFN-γ-Shh-BDNF pathway.

A wealth of evidence indicate that the peripheral immune activation alters brain development. However, it is still largely unclear whether and how peripheral immunosuppression affects neurodevelopment. Here, we found that the immunosuppressant cyclosporin A (CsA) decreased the number of BrdU+, BrdU+/DCX+, BrdU+/NeuN + cells in the hippocampus, impaired learning and memory and inhibited protein levels of the shh signaling pathway, including Shh, Smo and Gli1. However, the shh pathway receptor agonist SAG could block the impairment of cognitive ability and the decrease of hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) level induced by CsA. We also found that CsA decreased the level of interferon-gamma (IFN-γ), while up-regulation of IFN-γ altered the inhibitory effect of the shh signaling pathway and the decrease of BDNF induced by CsA. Collectively, these data indicate that peripheral CsA impairs neurogenesis and cognition in brain development through downregulating the IFN-γ-Shh-BDNF pathway. The present study guides us to correctly apply immunomodulatory drugs in early life and suggests that the IFN-γ-Shh-BDNF pathway may represent a novel protective target for neurodevelopment under the condition of immunosuppression.

Interferon-gamma Facilitates Neurogenesis by Activating Wnt/ß-catenin Cell Signaling Pathway via Promotion of STAT1 Regulation of the ß-Catenin Promoter.

Interferon-gamma (IFN-γ) is critical for central nervous system (CNS) functions and it may be a promising treatment to stimulate CNS regeneration. However, previous studies reported inconsistent results, and the molecular mechanisms remain controversial. Here we show that IFN-γ-treated mice via intraperitoneal injection have elevated IFN-γ level in central hippocampus and superior cognitive behaviors IFN-γ could activates the level of protein expression of Wnt7a, ß-catenin, and CyclinD1 in Wnt/ß-catenin signaling pathway of mice hippocampus. Functional and mechanism analysis in vitro revealed that IFN-γ promoted the proliferation and differentiation in primary cultured neural stem cells (NSCs). STAT1 was accountable for IFN-γ-induced activation of the ß-catenin promoter, and IFN-γ increased the binding affinity of STAT1 to ß-catenin promoter based on luciferase activity and chromatin immunoprecipitation. Our results suggest that IFN-γ exerts many effects ranging from cognitive function in vivo to NSC proliferation, self-renewal, and differentiation in vitro. It does so by recruiting STAT1 to the ß-catenin promoter, enhancing cis-regulation by STAT1, and ultimately activating Wnt/ß-catenin signaling. In this study, we first found that STAT1 was recruited into the promoter of ß-catenin to activate ß-catenin expression, and this effect was regulated by IFN-γ. It is also discovered firstly that Wnt/ß-catenin and JAK/STAT pathways form cross-links through STAT1. Promoting neurogenesis through immune stimulation might be a promising strategy for repairing the diseased/injured CNS. This study provides a scientific basis for immunomodulation to promote nerve regeneration and offer a new therapeutic direction for central nervous system regeneration.

Targeted Inhibition of the E3 Ligase SCFSkp2/Cks1 Has Antitumor Activity in RB1-Deficient Human and Mouse Small-Cell Lung Cancer.

The RB1 tumor suppressor gene is mutated in highly aggressive tumors including small-cell lung cancer (SCLC), where its loss, along with TP53, is required and sufficient for tumorigenesis. While RB1-mutant cells fail to arrest at G1-S in response to cell-cycle restriction point signals, this information has not led to effective strategies to treat RB1-deficient tumors, as it is challenging to develop targeted drugs for tumors that are driven by the loss of gene function. Our group previously identified Skp2, a substrate recruiting subunit of the SCF-Skp2 E3 ubiquitin ligase, as an early repression target of pRb whose knockout blocked tumorigenesis in Rb1-deficient prostate and pituitary tumors. Here we used genetic mouse models to demonstrate that deletion of Skp2 completely blocked the formation of SCLC in Rb1/Trp53-knockout mice (RP mice). Skp2 KO caused an increased accumulation of the Skp2-degradation target p27, a cyclin-dependent kinase inhibitor, which was confirmed as the mechanism of protection by using knock-in of a mutant p27 that was unable to bind to Skp2. Building on the observed synthetic lethality between Rb1 and Skp2, we found that small molecules that bind/inhibit Skp2 have in vivo antitumor activity in mouse tumors and human patient-derived xenograft models of SCLC. Using genetic and pharmacologic approaches, antitumor activity was seen with Skp2 loss or inhibition in established SCLC primary lung tumors, in liver metastases, and in chemotherapy-resistant tumors. Our data highlight a downstream actionable target in RB1-deficient cancers, for which there are currently no targeted therapies available. SIGNIFICANCE: There are no effective therapies for SCLC. The identification of an actionable target downstream of RB1, inactivated in SCLC and other advanced tumors, could have a broad impact on its treatment.

Origins of Beta Amyloid Differ Between Vascular Amyloid Deposition and Parenchymal Amyloid Plaques in the Spinal Cord of a Mouse Model of Alzheimer's Disease.

Cerebral amyloid angiopathy (CAA) refers to pathological changes occurring in cerebral blood vessels caused by deposition of beta amyloid (Aß) protein. However, the mechanisms involved in the origin of Aß for the formation of CAA and its link to parenchymal amyloid depositions remained to be unraveled. Here, we found CAA and parenchymal plaques distributed separately instead of mingling with each other in the spinal cord of TgCRND8 mice. Parenchymal plaques predominantly located in the dorsal horn whereas CAA distributed in the ventral horn. We further found that the ratio of Aß40/Aß42 was significantly higher in the ventral than that in the dorsal by ELISA assay, suggesting that origin of Aß forming parenchymal plaques may be different from that of CAA in the spinal cord. This hypothesis was further demonstrated by the surgical methods which indicated eliminating parenchymal plaques did not alter CAA in the affected spinal cord. We also examined the ratio of Aß40/Aß42 in the cerebral spinal fluid (CSF) in order to identify the origin of the CAA formation, and found the Aß40/Aß42 ratio was similar to that of CAA formation in the ventral horn. We further demonstrated that CSF tracer distributed along ventral horn vessels, in exactly the same pattern as Aß deposition in CAA in ventral part of spinal cord. These findings verified the concept that CSF influx may act as a constant source for delivering Aß, and contribute to the growth of paraarterial deposits in CAA. Taken together, the results of the present study highlight the important role of the Aß40/Aß42 ratio in determining vascular versus parenchymal amyloid deposition. Unlike parenchymal plaques, Aß of CAA comes from CSF; thus, manipulation of CSF Aß could represent a novel strategy to treat CAA.

Synergistic effects of combined vaccination with BCG and influenza vaccines on spatial cognition and hippocampal plasticity in rats.

Previous study has demonstrated the neurobeneficial role of BCG and influenza vaccines. Based on this, our study concentrated on the synergistic effects on development of central nervous system by combined vaccination with BCG and influenza vaccines in rats. Our results displayed that pups combinedly vaccinated with BCG and influenza vaccines showed a significant enhance in spatial cognition, induction of LTP, hippocampal neurogenesis and morphology of dendritic spines compared with pups vaccinated with BCG solely. Furthermore, combined vaccination with BCG and influenza vaccines showed higher expression of BDNF, IGF-1, IL-4, IFN-γ and lower IL-1ß, TNF-α and IL-6 than BCG. Taken together, combined vaccination with BCG and influenza vaccines presented synergistic effects on spatial cognition and hippocampal plasticity in rats.

Prenatal influenza vaccination rescues impairments of social behavior and lamination in a mouse model of autism.

BACKGROUND: Prenatal infection is a substantial risk factor for neurodevelopmental disorders such as autism in offspring. We have previously reported that influenza vaccination (VAC) during early pregnancy contributes to neurogenesis and behavioral function in offspring. RESULTS: Here, we probe the efficacy of VAC pretreatment on autism-like behaviors in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) mouse model. We show that VAC improves abnormal fetal brain cytoarchitecture and lamination, an effect associated with promotion of intermediate progenitor cell differentiation in MIA fetal brain. These beneficial effects are sufficient to prevent social deficits in adult MIA offspring. Furthermore, whole-genome analysis suggests a strong interaction between Ikzf1 (IKAROS family zinc-finger 1) and neuronal differentiation. Intriguingly, VAC rescues excessive microglial Ikzf1 expression and attenuates microglial inflammatory responses in the MIA fetal brain. CONCLUSIONS: Our study implies that a preprocessed influenza vaccination prevents maternal bacterial infection from causing neocortical lamination impairments and autism-related behaviors in offspring.

An enriched environment restores hepatitis B vaccination-mediated impairments in synaptic function through IFN-γ/Arginase1 signaling.

Activation of the neonatal immune system may contribute to deficits in neuronal plasticity. We have reported that neonatal vaccination with a hepatitis B vaccine (HBV) transiently impairs mood status and spatial memory involving a systemic T helper (Th) 2 bias and M1 microglial activation. Here, an EE induced microglial anti-inflammatory M2 polarization, as evidenced by selectively enhanced expression of the Arginase1 gene (Arg-1) in the hippocampus. Interestingly, knock-down of the Arg-1 gene prevented the effects of EE on restoring the dendritic spine density. Moreover, levels of the Th1-derived cytokine IFN-gamma (IFN-γ) were elevated in the choroid plexus (CP), which is the interface between the brain and the periphery. IFN-γ-blocking antibodies blunted the protective effects of an EE on spine density and LTP. Furthermore, levels of complement proteins C1q and C3 were elevated, and this elevation was associated with synapse loss induced by the HBV, whereas an EE reversed the effects of the HBV. Similarly, blockade of C1q activation clearly prevented synaptic pruning by microglia, LTP inhibition and memory deficits in hepatitis B-vaccinated mice. Together, the EE-induced increase in IFN-γ levels in the CP may disrupt systemic immunosuppression related to HBV via an IFN-γ/Arg-1/complement-dependent pathway.

Immunopotentiator Thymosin Alpha-1 Promotes Neurogenesis and Cognition in the Developing Mouse via a Systemic Th1 Bias.

In early life, the immune system plays an essential role in brain development. In our study, the immunopotentiator thymosin alpha-1 (Ta1) was peripherally administered to neonatal mice to explore whether the peripheral immunopotentiator affects neurodevelopment and cognition, and to further investigate the relevant mechanism. Compared with the control group, the Ta1 mice displayed better cognitive abilities in early life. The numbers of 5-bromodeoxyuridine (BrdU)+, nestin+, T-box transcription factor 2 (Tbr2)+, BrdU+/doublecortin (DCX)+, BrdU+/ionized calcium-binding adaptor molecule 1 (Iba1)+, and BrdU+/neuronal nuclei (NeuN)+ cells in the hippocampus were increased in the Ta1 group, accompanied by increased interleukin-4 (IL-4), interferon-gamma, brain-derived neurotrophic factor, nerve growth factor, and insulin-like growth factor-1 as well as decreased IL-6 and tumor necrosis factor-α. Furthermore, the Ta1-group showed a Th1-polarized immune response, and the neurotrophic factors were positively associated with the Th1/Th2 ratio. More importantly, administration of Ta1 blocked lipopolysaccharide-induced impairment of hippocampal neurogenesis in early life. These findings suggest that peripheral Ta1 contributes to neurogenesis and cognition probably through a systemic Th1 bias, as well as neuroprotection against LPS infection by Ta1.

Remodeling the Th1 polarized systemic environment contributes to neurogenesis and cognitive function via the Wnt7a pathway in neonatal mice.

Neonatal Bacillus Calmette-Guérin (BCG) vaccination results in a positive effect on hippocampal neurogenesis and cognition. Serum cytokines are considered to be the chief culprit. In this study, serum from BCG-treated mice was identified as Th1 polarized serum. The serum showed an increased ratio of IFN-γ to IL-4 and decreased levels of TNF-α and IL-6. After Th1 polarized serum was injected intraperitoneally into postnatal mice, the levels of cytokines and ratio of IFN-γ to IL-4 in the serum and hippocampus of postnatal mice showed a similar alteration as those in Th1 polarized serum. This result indicated that the immune homeostatic milieu in postnatal mice was broken and the Th1 polarized systemic environment in the BCG-serum group was remodeled. The BCG-serum group displayed more BrdU+/DCX+ cells, BrdU+/NeuN+ cells, Nestin+ cells and better cognitive abilities. In neural stem cells, the Wnt7a/ß-catenin signaling pathway was activated and exposure to the Wnt7a antagonist Dickkopf-1 inhibited BCG-serum-induced Wnt7a/ß-catenin signaling, neurogenesis and cognitive function. Additionally, BCG-serum was associated with elevations in hippocampal brain-derived neurotrophic factor (BDNF) levels, and BDNF expression in the BCG-serum group was offset by Dickkopf-1 treatment. By rebalancing the Th1 polarized systemic environment in neonatal mice, it is possible that treatment with BCG-serum promotes hippocampal neurogenesis and improves cognitive functions, which are associated with Wnt7a/ß-catenin-BDNF signaling.

Immunization with Bacillus Calmette-Guérin (BCG) alleviates neuroinflammation and cognitive deficits in APP/PS1 mice via the recruitment of inflammation-resolving monocytes to the brain.

The immune system plays a crucial role in the progression of Alzheimer's disease (AD). Recently, immune-dependent cascade induced by systemic immune activation has been verified to play a beneficial role in AD mouse models. Here, we tested whether Bacillus Calmette-Guérin (BCG) immunization alters AD pathology and cognitive dysfunction in APP/PS1 AD mouse model, and with 4Aß1-15 vaccination as positive control. It was found that BCG treatment reversed the cognitive decline to the extent observed in 4Aß1-15 group, but did not reduce the ß-amyloid (Aß) burden in the brain. Then, we demonstrated the enhanced recruitment of inflammation-resolving monocytes across the choroid plexus and perivascular spaces to cerebral sites of plaque pathology in APP/PS1 mice immunized with BCG. Furthermore, elevated splenocyte Foxp3+ regulatory T cell levels in the control APP/PS1 mice were down-regulated back to the wild-type (WT) levels by BCG treatment but not 4Aß1-15 vaccination. In addition, BCG treatment induced the production of more circulating interferon (IFN)-γ than the controls and 4Aß1-15 vaccination. Though the similar reductions in brain levels of pro-inflammatory cytokines were observed in the BCG and 4Aß1-15 groups compared to the controls, only BCG had the great effect in upregulating cerebral anti-inflammatory cytokine levels as well as elevating the expression of neurotrophic factors in the brain of APP/PS1 mice. Thus, it is suggested that BCG exerts a beneficial immunomodulatory effect in APP/PS1 mice through mitigation of systemic immune suppression, induction of IFN-γ response and alleviation of the neuroinflammatory response.

Combined effect of BCG vaccination and enriched environment promote neurogenesis and spatial cognition via a shift in meningeal macrophage M2 polarization.

BACKGROUND: The spatial learning abilities of developing mice benefit from extrinsic cues, such as an enriched environment, with concomitant enhancement in cognitive functions. Interestingly, such enhancements can be further increased through intrinsic Bacillus Calmette-Guérin (BCG) vaccination. RESULTS: Here, we first report that combined neonatal BCG vaccination and exposure to an enriched environment (Enr) induced combined neurobeneficial effects, including hippocampal long-term potentiation, and increased neurogenesis and spatial learning and memory, in mice exposed to the Enr and vaccinated with BCG relative to those in the Enr that did not receive BCG vaccination. Neonatal BCG vaccination markedly induced anti-inflammatory meningeal macrophage polarization both in regular and Enr breeding mice. The meninges are composed of the pia mater, dura mater, and choroid plexus. Alternatively, this anti-inflammatory activity of the meninges occurred simultaneously with increased expression of the neurotrophic factors BDNF/IGF-1 and the M2 microglial phenotype in the hippocampus. Our results reveal a critical role for BCG vaccination in the regulation of neurogenesis and spatial cognition through meningeal macrophage M2 polarization and neurotrophic factor expression; these effects were completely or partially prevented by minocycline or anti-IL-10 antibody treatment, respectively. CONCLUSIONS: Together, we first claim that immunological factor and environmental factor induce a combined effect on neurogenesis and cognition via a common pathway-meningeal macrophage M2 polarization. We also present a novel functional association between peripheral T lymphocytes and meningeal macrophages after evoking adaptive immune responses in the periphery whereby T lymphocytes are recruited to the meninges in response to systemic IFN-γ signaling. This leads to meningeal macrophage M2 polarization, subsequent to microglial M2 activation and neurotrophic factor expression, and eventually promotes a positive behavior.