Infiltration Of Peripheral Immune Cells Research Articles

A novel small-molecular CCR5 antagonist promotes neural repair after stroke.

Chemokine receptor 5 (CCR5) is one of the main co-receptors of HIV-1, and has been found to be a potential therapeutic target for stroke. Maraviroc is a classic CCR5 antagonist, which is undergoing clinical trials against stroke. As maraviroc shows poor blood-brain barrier (BBB) permeability, it is of interest to find novel CCR5 antagonists suitable for neurological medication. In this study we characterized the therapeutic potential of a novel CCR5 antagonist A14 in treating ischemic stroke mice. A14 was discovered in screening millions compounds in the Chemdiv library based on the molecular docking diagram of CCR5 and maraviroc. We found that A14 dose-dependently inhibited the CCR5 activity with an IC50 value of 4.29 μM. Pharmacodynamic studies showed that A14 treatment exerted protective effects against neuronal ischemic injury both in vitro and vivo. In a SH-SY5Y cell line overexpressing CCR5, A14 (0.1, 1 μM) significantly alleviated OGD/R-induced cell injury. We found that the expression of CCR5 and its ligand CKLF1 was significantly upregulated during both acute and recovery period in focal cortical stroke mice; oral administration of A14 (20 mg·kg-1·d-1, for 1 week) produced sustained protective effect against motor impairment. A14 treatment had earlier onset time, lower onset dosage and much better BBB permeability compared to maraviroc. MRI analysis also showed that A14 treatment significantly reduced the infarction volume after 1 week of treatment. We further revealed that A14 treatment blocked the protein-protein interaction between CCR5 and CKLF1, increasing the activity of CREB signaling pathway in neurons, thereby improving axonal sprouting and synaptic density after stroke. In addition, A14 treatment remarkably inhibited the reactive proliferation of glial cells after stroke and reduced the infiltration of peripheral immune cells. These results demonstrate that A14 is a promising novel CCR5 antagonist for promoting neuronal repair after ischemic stroke. A14 blocked the protein-protein interaction between CKLF1 and CCR5 after stroke by binding with CCR5 stably, improved the infarct area and promoted motor recovery through reversing the CREB/pCREB signaling which was inhibited by activated CCR5 Gαi pathway, and benefited to the dendritic spines and axons sprouting.

Stress promotes the infiltration of peripheral immune cells to the brain

Immune cells and the brain have a privileged interaction. Here, we report changes in the hippocampal immune microenvironment at the single cell level after stress, uncovering the tight orchestration of immune cell infiltration into the hippocampus after stress to maintain homeostasis. We show the distribution of several immune cell types in the hippocampus associated with their susceptibility or resilience to the learned helplessness paradigm in a sex- and microbiota-dependent manner using single-cell RNA sequencing and bioinformatic tools, flow cytometry, and immunofluorescence. We uncovered the presence of tissue-resident memory T cells that accumulate over time in the hippocampus of learned helpless mice, and the presence of CD74-expressing myeloid cells. These cells were found by a knockdown approach to be critical to induce resilience to learned helplessness. Altogether, these findings provide a novel overview of the neuro-immune repertoire and its impact on the landscape of the hippocampus after learned helplessness.

Regulation of the PD-1/PD-L1 axis in relapsing-remitting Multiple Sclerosis (P2-3.001)

<h3>Objective:</h3> The PD-1/PD-L1 (programmed cell death protein 1/programmed cell death ligand 1) axis plays an important role in the adaptive immune system and has influence on neoplastic and inflammatory diseases. The role of the PD-1/PD-L1 axis in multiple sclerosis (MS) has not yet been investigated in detail. We aimed to delineate distinct expression patterns in peripheral blood mononuclear cell (PBMC) subsets and to evaluate the role of soluble PD-1/PD-L1 in the context of MS. <h3>Background:</h3> PD-L1/PD-1 also exist in soluble forms (sPD-L1/sPD-1) shedded from cellular surfaces. In systemic autoimmune diseases, sPD-1/sPD-L1 serum levels and membrane-bound PD-1/PD-L1 on T and antigen-presenting cells are linked to disease activity and treatment response. In MS, the PD-1/PD-L1 axis and in particular the role of soluble PD-1/PD-L1 is poorly understood but may offer relevance as disease marker and potential target for therapeutic intervention. <h3>Design/Methods:</h3> In depth immunophenotyping by flow cytometry was performed on PBMCs of 49 patients with relapsing-remitting MS (RRMS) and 27 controls. sPD-1/sPD-L1 serum levels were analyzed in a cohort of 84 patients with RRMS and 36 controls. To evaluate the therapeutic potential of soluble PD-L1, 600 μg/kg recombinant protein was systemically administered in Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. <h3>Results:</h3> Patients with RRMS displayed distinct cellular PD-1/PD-L1 expression patterns in PBMCs and an association of sPD-L1 with MS subtype and disease severity. Systemic administration of recombinant PD-L1 in EAE resulted in ameliorated disease severity and reduced infiltration of peripheral immune cells into the CNS. <h3>Conclusions:</h3> The marked expression of PD-1/PD-L1 in immune cell subsets of patients with RRMS, and the correlation of sPD-L1 with disease-severity offers promising potential for the use as a serum marker in the context of MS. Furthermore, enhancement of coregulatory PD-1/PD-L1 signaling by exogenous supplementation of sPD-L1 may serve as a novel therapeutic strategy for severe stages of acute neuroinflammation. <b>Disclosure:</b> Dr. Tsaktanis has nothing to disclose. Mr. Linnerbauer has nothing to disclose. Mrs. Loesslein has nothing to disclose. Prof. Hemmer has received personal compensation in the range of $0-$499 for serving as a Consultant for Vaccitech. Prof. Hemmer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Prof. Hemmer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Polpharma. Prof. Hemmer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Prof. Hemmer has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Allergy Care. The institution of Prof. Hemmer has received research support from Regeneron. The institution of Prof. Hemmer has received research support from German Research Foundation. The institution of Prof. Hemmer has received research support from German Ministry for Education and Research. The institution of Prof. Hemmer has received research support from European Commission. Prof. Hemmer has received intellectual property interests from a discovery or technology relating to health care. Prof. Hemmer has received intellectual property interests from a discovery or technology relating to health care. Mark Mühlau has nothing to disclose. Dr. Quintana has nothing to disclose. Prof. Rothhammer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Prof. Rothhammer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. The institution of Prof. Rothhammer has received research support from German Research Foundation. The institution of Prof. Rothhammer has received research support from European Research Council.

Bruton tyrosine kinase inhibitors for multiple sclerosis.

Current therapies for multiple sclerosis (MS) reduce both relapses and relapse-associated worsening of disability, which is assumed to be mainly associated with transient infiltration of peripheral immune cells into the central nervous system (CNS). However, approved therapies are less effective at slowing disability accumulation in patients with MS, in part owing to their lack of relevant effects on CNS-compartmentalized inflammation, which has been proposed to drive disability. Bruton tyrosine kinase (BTK) is an intracellular signalling molecule involved in the regulation of maturation, survival, migration and activation of B cells and microglia. As CNS-compartmentalized B cells and microglia are considered central to the immunopathogenesis of progressive MS, treatment with CNS-penetrant BTK inhibitors might curtail disease progression by targeting immune cells on both sides of the blood-brain barrier. Five BTK inhibitors that differ in selectivity, strength of inhibition, binding mechanisms and ability to modulate immune cells within the CNS are currently under investigation in clinical trials as a treatment for MS. This Review describes the role of BTK in various immune cells implicated in MS, provides an overview of preclinical data on BTK inhibitors and discusses the (largely preliminary) data from clinical trials.

Astrocyte Immune Functions and Glaucoma.

Astrocytes, a non-neuronal glial cell type in the nervous system, are essential for regulating physiological functions of the central nervous system. In various injuries and diseases of the central nervous system, astrocytes often change their phenotypes into neurotoxic ones that participate in pro-inflammatory responses (hereafter referred to as "immune functions"). Such astrocytic immune functions are not only limited to brain diseases but are also found in ocular neurodegenerative diseases such as glaucoma, a retinal neurodegenerative disease that is the leading cause of blindness worldwide. The eye has two astrocyte-lineage cells: astrocytes and Müller cells. They maintain the physiological environment of the retina and optic nerve, thereby controlling visual function. Dysfunction of astrocyte-lineage cells may be involved in the onset and progression of glaucoma. These cells become reactive in glaucoma patients, and animal studies have suggested that their immune responses may be linked to glaucoma-related events: tissue remodeling, neuronal death, and infiltration of peripheral immune cells. In this review, we discuss the role of the immune functions of astrocyte-lineage cells in the pathogenesis of glaucoma.

Abstract TP170: Heterochronic Parabiosis Lowers Microglia Activation And Myeloid Infiltration In Aged Parabiont

Introduction: Of the 795,000 people who suffer strokes annually, 75% are over the age of 65. Aging is a major risk factor for stroke. The risk of stroke doubles every decade after the age of 55. Aging leads to dramatic changes in peripheral myeloid cells and increases the activation state of microglia in the brain. Although age is an important determinant of stroke susceptibility and outcome, the contribution from the aged immune system remains unclear. Hypothesis: We hypothesize that aged mice (18-22 mo) parabionts paired with a young parabiont (2-3 mo) would have less microglia activation due to exposure to systemic factors from young mice when compared to aged mice paired with aged mice (18-22 mo). Methods: Young Pep-boy mice (haplotype CD45.1) were surgically paired with aged mice (haplotype CD45.2) for two months. The brains of these mice were then subjected to flow cytometry analysis. Brain single cell suspensions were isolated and immunophenotyped with a microglia specific panel. Results: Our results show that myeloid infiltration was decreased in the aged parabiont (paired with a young mouse) compared to its naïve counterpart (n=3-6/ grp, p = 0.0036). Microglia activation was assessed utilizing a homeostatic marker, P2RY12, and a microglia specific marker, Tmem119. Interestingly, the expression of Tmem119 on CD45 int CD11b + cells was significantly increased in the aged parabionts compared to aged, naïve mice (n=3-6/ grp, p =0.0006), however, P2RY12 trended upward in the aged parabiont (n=3/6 /grp, p =0.0742). This suggests that the shared circulation created between the heterochronic pair led to a reduction in immune activation in the aged parabiont. Thus, the young parabiont allows the aged parabiont access to rejuvenating factors through the shared flow of blood which reduced neuroinflammation. Conclusion: Future studies are needed to identify the specific factors contributing to reduced microglial activation and lowered infiltration of peripheral immune cells induced by pairing with young animals. Studies examining the immune response to stroke in young and aged parabionts are needed.

Massive Loss of Proprioceptive Ia Synapses in Rat Spinal Motoneurons after Nerve Crush Injuries in the Postnatal Period.

Peripheral nerve injuries (PNIs) induce the retraction from the ventral horn of the synaptic collaterals of Ia afferents injured in the nerve, effectively removing Ia synapses from α-motoneurons. The loss of Ia input impairs functional recovery and could explain, in part, better recovery after PNIs with better Ia synaptic preservation. Synaptic losses correlate with injury severity, speed, and efficiency of muscle reinnervation and requires ventral microglia activation. It is unknown whether this plasticity is age dependent. In neonates, axotomized motoneurons and sensory neurons undergo apoptosis, but after postnatal day 10 most survive. The goal of this study was to analyze vesicular glutamate transporter 1 (VGluT1)-labeled Ia synapses (which also include II afferents) after nerve crush in 10 day old rats, a PNI causing little Ia/II synapse loss in adult rats. We confirmed fast and efficient reinnervation of leg muscles; however, a massive number of VGluT1/Ia/II synapses were permanently lost. This synapse loss was similar to that after more severe nerve injuries involving full transection in adults. In adults, disappearance of ventrally directed Ia/II collaterals targeting α-motoneurons was associated with a prolonged microglia reaction and a CCR2 mechanism that included infiltration of CCR2 blood immune cells. By contrast, microgliosis after P10 injuries was fast, resolved in about a week, and there was no evidence of peripheral immune cell infiltration. We conclude that VGluT1/Ia/II synapse loss in young animals differs in mechanism, perhaps associated with higher microglia synaptic pruning activity at this age and results in larger losses after milder nerve injuries.

1,2-13C2-Glucose Tracing Approach to Assess Metabolic Alterations of Human Monocytes under Neuroinflammatory Conditions.

Neuroinflammation is one of the common features in most neurological diseases including multiple sclerosis (MScl) and neurodegenerative diseases such as Alzheimer's disease (AD). It is associated with local brain inflammation, microglial activation, and infiltration of peripheral immune cells into cerebrospinal fluid (CSF) and the central nervous system (CNS). It has been shown that the diversity of phenotypic changes in monocytes in CSF relates to neuroinflammation. It remains to be investigated whether these phenotypic changes are associated with functional or metabolic alteration, which may give a hint to their function or changes in cell states, e.g., cell activation. In this article, we investigate whether major metabolic pathways of blood monocytes alter after exposure to CSF of healthy individuals or patients with AD or MScl. Our findings show a significant alteration of the metabolism of monocytes treated with CSF from patients and healthy donors, including higher production of citric acid and glutamine, suggesting a more active glycolysis and tricarboxylic acid (TCA) cycle and reduced production of glycine and serine. These alterations suggest metabolic reprogramming of monocytes, possibly related to the change of compartment (from blood to CSF) and/or disease-related. Moreover, the levels of serine differ between AD and MScl, suggesting different phenotypic alterations between diseases.

Neuroinflammation and brain-peripheral interaction in ischemic stroke: A narrative review.

Excessive immune activation within the lesion site can be observed after stroke onset. Such neuroinflammation within the brain parenchyma represents the innate immune response, as well as the result of the additional interactions between peripheral and resident immune cells. Accumulative studies have illustrated that the pathological process of ischemic stroke is associated with resident and peripheral immunity. The infiltration of peripheral immune cells within the brain parenchyma implicitly contributes to secondary brain injuries. Therefore, better understanding of the roles of resident and peripheral immune reactions toward ischemic insult is necessary. In this review, we summarized the interaction between peripheral and resident immunity on systemic immunity and the clinical outcomes after stroke onset and also discussed various potential immunotherapeutic strategies.

Notch signaling pathway-based classification of bladder cancer in relation to tumor immune infiltration.

The role of the Notch signaling pathway in the development of various tumors has received increasing attention, but the relationship between the Notch signaling pathway and the prognosis of bladder cancer has rarely been studied. The aim of this study was to investigate the function and risk evaluation value of Notch signaling pathway-related genes (NRGs) in bladder cancer. The list of genes related to the Notch signaling pathway was obtained from the molecular signature database. The bladder cancer dataset was obtained from The Cancer Genome Atlas (TCGA) database. Cox regression analysis and Lasso regression analysis were used to construct the characteristics for predicting the overall survival of patients with bladder cancer. The CIBERSORT algorithm was used to evaluate the infiltration of peripheral immune cells in different risk subgroups. NRG expression was remarkably dysregulated in bladder cancer. Next, bladder cancer was classified into two subtypes (C1 and C2) based on NRG expression levels. The two subtypes had a significant difference in prognosis and were closely related to clinical characteristics. Further analysis showed that immune cell infiltration and immune scores were also significantly different between the two subtypes. Notch signaling pathway-based bladder cancer typing has different prognoses and may be related to tumor immunity. NRGs can be identified for risk evaluation and help improve clinical decision-making.

HMBOX1, a member of the homeobox family: current research progress.

Homeobox containing 1 (HMBOX1) is a transcription factor that was identified in 2006 from a cDNA library of the human pancreas. It belongs to the HNF gene class of the homeobox family. HMBOX1 is widely expressed in normal human tissues; however, its expression level is rather uneven. Homeobox members have been widely reported to participate in embryonic development and differentiation as well as in pathological and physiological processes. Although research on the role of HMBOX1 is still in its infancy, many reports have revealed its regulatory role in cell differentiation, immune regulation, inflammation, and tumor progression. HMBOX1 plays an important role in promoting the differentiation of bone marrow stromal stem cells (BMSCs) into endothelial cells and contributes to their physiological functions. As an immunoregulatory factor, HMBOX1 can significantly inhibit the inflammatory response in hepatocytes and NK cells and impede the infiltration of peripheral immune cells to the liver. In tumor development, HMBOX1 exerts diametrically opposite biological functions, inhibiting or promoting the process. HMBOX1 possesses complex and diverse biological functions. In this review, we provide a brief overview of the research on HMBOX1.

Autoimmune Mechanisms in Focal Epilepsy of Unknown Cause

ABSTRACT The manifestation of immunological findings in diverse disorders presenting with seizures points to autoimmunity and inflammation in the etiology of epilepsy. Typical examples of autoimmunity-associated epilepsy are autoimmune encephalitis, Rasmussen encephalitis, and glutamic acid decarboxylase (GAD) antibody-positive temporal lobe epilepsy (TLE). The last entity is a typical example of antibody-positive focal epilepsy of unknown cause (FEUC). One of the most prominent findings emphasizing the coexistence of epilepsy and autoimmunity is the detection of anti-neuronal antibodies in patients manifesting with seizures. Emergence of antibody-producing plasma cells in the early course of GAD-antibody-positive TLE and induction of seizures in rodents upon intracerebral administration of N-methyl-D-aspartate receptor antibodies indicate that anti-neuronal antibodies may play a causal (rather than bystander) role in the induction of seizures. By contrast, innate immunity of the central nervous system (CNS) and infiltrating cytotoxic T-cells appear to participate in Rasmussen encephalitis and autoimmune encephalitis with antibodies to intracellular antigens. In addition, repetitive seizures may activate glial cells through the release of damage-associate molecular pattern mediators and activation of toll-like receptors, which in turn leads to disrupted blood–brain barrier and increased cerebral infiltration of peripheral blood immune cells. In conclusion, complex interactions of humoral and cellular immunity in the CNS appear to cause or at least contribute to seizure induction in FEUC. The nature of these interactions has recently started to be understood. Investigation of these mechanisms is substantial for the discovery of new treatment strategies and biomarkers in epilepsy.

Role of NLRP3 inflammasome in diabetic neuropathy and prevention and treatment with traditional Chinese medicine

As one of the most frequent complications of diabetes, diabetic neuropathy often involves peripheral and central nervous systems. Neuroinflammation is the key pathogenic factor of secondary nerve injury in diabetes. NOD-like receptor pyrin domain-containing 3(NLRP3) inflammasome is a group of subcellular multiprotein complexes, including NLRP3, apoptosis associated speck-like protein(ASC), and pro-cysteinyl aspartate specific proteinase 1(pro-caspase-1). NLRP3 inflammasome is an inducer of innate immune responses. Its activation stimulates the inflammatory cascade reaction, promotes the release of inflammatory mediators, triggers cell death and uncontrolled autophagy, activates glial cells, facilitates peripheral immune cell infiltration, and initiates amyoid β(Aβ)-tau cascade reactions. As a result, it contributes to the central nerve, somatic nerve, autonomic nerve, and retinal nerve cell damage secondary to diabetes. Therefore, due to its key role in the neuroinflammation responses of the body, NLRP3 inflammasome may provide new targets for the treatment of diabetic neuropathy. With multi-target and low-toxicity advantages, traditional Chinese medicine plays a vital role in the treatment of diabetic neuropathy. Accumulating evidence has shown that traditional Chinese medicine exerts curative effects on diabetic neuropathy possibly through regulating NLRP3 inflammasome. Although the role of NLRP3 inflammasome in diabetes and related complications has been investigated in the literature, systematical studies on drugs and mechanism analysis for secondary neuropathy are still lacking. In this article, the role of NLRP3 inflammasome in diabetic neuropathy was explored, and the research progress on traditional Chinese medicine in the treatment of diabetic neuropathy through NLRP3 inflammasome was reviewed.

Annexin A5 ameliorates traumatic brain injury-induced neuroinflammation and neuronal ferroptosis by modulating the NF-ĸB/HMGB1 and Nrf2/HO-1 pathways.

Traumatic brain injury often causes poor outcomes and has few established treatments. Neuroinflammation and ferroptosis hinder therapeutic progress in this domain. Annexin A5 (A5) has anticoagulant, anti-apoptotic and anti-inflammatory bioactivities. However, its protective effects on traumatic brain injury remain unclear. Thus, we explored whether inhibiting ferroptosis and neuroinflammation using A5 could ameliorate traumatic brain injury. We injected recombinant A5 (50µg/kg) in the tail vein of mice 30min after fluid percussion injury. We then assessed modified neurologic severity scores, Morris water maze performance, rotarod test performance, brain water content, and blood-brain barrier permeability to document the neuroprotective effects of A5. Two days after the traumatic brain injury, we collected injured cortex tissues for western blot, Perl's staining, apoptosis staining, Nissl staining, immunofluorescence/immunohistochemistry, and enzyme-linked immunosorbent assay. We also quantified superoxide dismutase and glutathione peroxidase activity and glutathione and malondialdehyde levels. A5 improved neurological deficits, weight loss, cerebral hypoperfusion, brain edema, blood-brain barrier disruption, neuronal apoptosis, and ferroptosis. It also increased the ratio of M2/M1 phenotype microglia, reduced interleukin 1β and 6 levels, decreased peripheral immune cell infiltration, and increased interleukin 10 levels. A5 reduced neuronal iron accumulation, p53-related cell death, and oxidative stress damage. Finally, A5 downregulated HMGB1 and NF-ĸB pathways and upregulated the nuclear erythroid 2-related factor (Nrf2) and HO-1 pathways. These results suggest that A5 exerts neuroprotection in traumatic brain injury mice and ameliorates neuroinflammation, oxidative stress, and ferroptosis by regulating the NF-kB/HMGB1 pathway and the Nrf2/HO-1 antioxidant system.

Mediterranean Diet and Parkinson’s Disease

Parkinson's disease (PD) is an age-related neurodegenerative disorder, diagnosed on the basis of typical motor disturbances, but also characterized by the presence of non-motor symptoms, such as rapid eye movement (REM)-sleep behavior disorders, olfactory impairment, and constipation, which are often prodromal to the onset of the disease. PD is often associated with the presence of oxidative brain injury and chronic neuroinflammation, with infiltration and accumulation of peripheral immune cells that have been found in affected brain regions of PD patients. Recently, the role of the gut-brain axis in the pathogenesis of PD is getting more and more attention, and several pieces of evidence indicate alterations in the gut microbiota of PD-affected patients. Diet exerts a central role in defining the microbiota composition and different dietetic patterns can result in a higher or lower abundance of specific bacteria that, in turn, can affect gut permeability and express anti- or pro-inflammatory metabolites. In the present review, the effects of the Mediterranean diet in modulating both PD onset and its progression will be considered with a special focus on the antioxidant and anti-inflammatory properties of this dietetic regimen as well as on its effects on the microbiota composition.

TNF and IL6/Jak2 signaling pathways are the main contributors of the glia-derived neuroinflammation present in Lafora disease, a fatal form of progressive myoclonus epilepsy

Lafora disease (LD; OMIM#254780) is a rare form of progressive myoclonus epilepsy (prevalence <1:1,000,000) characterized by the accumulation of insoluble deposits of aberrant glycogen (polyglucosans), named Lafora bodies, in the brain but also in peripheral tissues. LD is the most severe form of the group of progressive myoclonus epilepsies, since patients present a rapid deterioration and dementia with amplification of seizures, leading to death after a decade from the onset of the first symptoms. We have recently described that reactive glia-derived neuroinflammation should be considered a novel hallmark of LD since we observed a florid upregulation of differentially expressed genes in both LD mouse lines, which were mainly related to mediators of inflammatory response. In this work, we define an upregulation of the expression of mediators of the TNF and IL6/JAK2 signaling pathways in LD. In addition, we describe the activation of the non-canonical form of the inflammasome. Furthermore, we describe the infiltration of peripheral immune cells in the brain parenchyma, which could aggravate glia-derived neuroinflammation. Finally, we describe CXCL10 and S100b as blood biomarkers of the disease, which will allow the study of the progression of the disease using serum blood samples. We consider that the identification of these initial inflammatory changes in LD will be very important to implement possible anti-inflammatory therapeutic strategies to prevent the development of the disease.

Single cell sequencing revealed the mechanism of PD-1 resistance affected by the expression profile of peripheral blood immune cells in ESCC.

Esophageal squamous carcinoma (ESCC) is a highly lethal malignancy with poor prognosis. The effect of transcriptome characteristics of patient immune microenvironment (TME) on the efficacy of immunosuppressive agents is still poorly understood. Here we extracted and isolated immune cells from peripheral blood of patients with PD-1 monoclonal antibody sensitivity and resistance, and conducted deep single-cell RNA sequencing to describe the baseline landscape of the composition, lineage, and functional status of infiltrating immune cells in peripheral blood of patients with esophageal cancer. The transcriptome characteristics of immune cells were comprehensively analyzed, and the dynamic changes of cell percentage, heterogeneity of cell subtypes and interactions between cells were explained. Co-expression and pedigree tracking based on T-cell antigen receptors revealed a significant proportion of highly migratory intertissue-effector T cells. GO and KEGG enrichment pathway Analysis of CD8+ effect-T cells ESCC_S group and ESCC_D1,2 group, found that in the up-regulated enrichment pathway, ESCC_S group enriched more PD-L1 and PD-1 checkpoint pathways expressed in tumors (JUN/NFKBIA/FOS/KRAS/IFNG), which also exist in T cell receptor signaling pathways. MT2A, MT1X and MT1E were differentially expressed in ESCC patients with PD-1 monoclonal antibody resistance, which may be related to the resistance of PD-1 mMAB. This study has an in-depth understanding of the influence of peripheral immune cell infiltration on the sensitivity of monoclonal antibody PD-1 in patients with esophageal cancer, which is helpful to promote the immunotherapy of patients with esophageal cancer.

CXCR4 knockout induces neuropathological changes in the MPTP-lesioned model of Parkinson's disease

C-X-C chemokine receptor type 4 (CXCR4) is highly expressed in Parkinson's disease (PD) mice's brains and is related to astrocyte signaling and microglial activation. This makes CXCR4 related to neuroinflammation and also makes CXCR4 considered to be the PD development mechanism and possible therapeutic targets. Therefore, it is worth studying the effect of CXCR4 on neuropathological changes and its potential therapeutic value for PD. This study aimed to investigate the effect of CXCR4 knockout on neuropathological changes in the mouse model of PD and its mechanism. In this study, CXCR4-WT and CXCR4+/− C57BL mice were used to make Parkinson's model. Behavioral experiments, dopaminergic neuron markers, neuroinflammation, and blood-brain barrier damage were detected to verify the effect of CXCR4 knockout on neuropathological changes. CXCR4 knockout improved the behavioral results and tyrosine hydroxylase (TH) expression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice. In the substantia nigra (SN) area of the brain of PD mouse model, the number of Iba1-positive (p = 0.0004) and GFAP-positive cells (p = 0.0349) was significantly lower in CXCR4 knockout group than CXCR4-WT group. CXCR4 knockout reduced MPTP-induced infiltration of peripheral immune cells and the expression of pro-inflammatory cytokines. CXCR4 knockout also protected blood-brain barrier (BBB) from MPTP-induced damage. In conclusion, CXCR4 knockout inhibits the degeneration of dopamine neurons, microglial and astrocyte activation, neuroinflammation, and BBB damages in the MPTP-lesioned PD mice.

Transcriptomic Profiling Identifies CD8+ T Cells in the Brain of Aged and Alzheimer's Disease Transgenic Mice as Tissue-Resident Memory T Cells.

Peripheral immune cell infiltration into the brain is a prominent feature in aging and various neurodegenerative diseases such as Alzheimer's disease (AD). As AD progresses, CD8+ T cells infiltrate into the brain parenchyma, where they tightly associate with neurons and microglia. The functional properties of CD8+ T cells in the brain are largely unknown. To gain further insights into the putative functions of CD8+ T cells in the brain, we explored and compared the transcriptomic profile of CD8+ T cells isolated from the brain and blood of transgenic AD (APPswe/PSEN1dE9, line 85 [APP-PS1]) and age-matched wild-type (WT) mice. Brain CD8+ T cells of APP-PS1 and WT animals had similar transcriptomic profiles and substantially differed from blood circulating CD8+ T cells. The gene signature of brain CD8+ T cells identified them as tissue-resident memory (Trm) T cells. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis on the significantly upregulated genes revealed overrepresentation of biological processes involved in IFN-β signaling and the response to viral infections. Furthermore, brain CD8+ T cells of APP-PS1 and aged WT mice showed similar differentially regulated genes as brain Trm CD8+ T cells in mouse models with acute virus infection, chronic parasite infection, and tumor growth. In conclusion, our profiling of brain CD8+ T cells suggests that in AD, these cells exhibit similar adaptive immune responses as in other inflammatory diseases of the CNS, potentially opening the door for immunotherapy in AD.

Assessing the Sustainability of an Integrated Rural Sanitation and Hygiene Approach: A Repeated Cross-Sectional Evaluation in 10 Countries.

While many studies have implemented programs to increase sanitation coverage throughout the world, there are limited rigorous studies on the sustainability of these sanitation programs. Between 2014 and 2018, the rural Sustainable Sanitation and Hygiene for All (SSH4A) approach was implemented by SNV in sub-Saharan Africa and Asia. Repeated cross-sectional household surveys were administered annually throughout program implementation and 1 to 2 years following completion of program activities. We characterize to what extent sanitation coverage was sustained 1 to 2 years after implementation of this SSH4A intervention. Surveys were conducted in 12 program areas in 10 countries, with 22,666 households receiving a post-implementation survey. Six of 12 program areas (Bhutan, Ghana, Kenya, both Nepal sites, Tanzania) had similar coverage levels of basic sanitation 1-2 years post-implementation, whereas there were varying levels of slippage in the other program areas (both Ethiopia sites, Indonesia, Mozambique, Uganda, Zambia), ranging from a drop of 63 percentage points in coverage in Ethiopia to a drop of only 4 percentage points in Indonesia. In countries that experienced losses in the coverage of household sanitation, sanitation sharing among neighbors generally did not increase, whereas open defecation did increase. In each of the areas where slippage occurred, the sanitation coverage levels at the final time point were all still higher than the initial time point before SNV started working in these areas. We found several factors to be associated with the sustainability of sanitation coverage, including household socioeconomic status, having household members with disabilities, baseline sanitation coverage levels of the program areas, and rate of change of coverage during program activities. Data revealed sustained gains in sanitation coverage in some program areas, yet slippage in other areas. This work may serve to benchmark the sustainability of sanitation interventions in sub-Saharan Africa and Asia.