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Frontiers in Immunology 2024Therapeutic antibodies have become a major strategy to treat oncologic diseases. For chronic lymphocytic leukemia, antibodies against CD20 are used to target and elicit...
INTRODUCTION
Therapeutic antibodies have become a major strategy to treat oncologic diseases. For chronic lymphocytic leukemia, antibodies against CD20 are used to target and elicit cytotoxic responses against malignant B cells. However, efficacy is often compromised due to a suppressive microenvironment that interferes with cellular immune responses. To overcome this suppression, agonists of pattern recognition receptors have been studied which promote direct cytotoxicity or elicit anti-tumoral immune responses. NOD2 is an intracellular pattern recognition receptor that participates in the detection of peptidoglycan, a key component of bacterial cell walls. This detection then mediates the activation of multiple signaling pathways in myeloid cells. Although several NOD2 agonists are being used worldwide, the potential benefit of these agents in the context of antibody therapy has not been explored.
METHODS
Primary cells from healthy-donor volunteers (PBMCs, monocytes) or CLL patients (monocytes) were treated with versus without the NOD2 agonist L18-MDP, then antibody-mediated responses were assessed. In vivo, the Eµ-TCL1 mouse model of CLL was used to test the effects of L18-MDP treatment alone and in combination with anti-CD20 antibody.
RESULTS
Treatment of peripheral blood mononuclear cells with L18-MDP led to activation of monocytes from both healthy donors and CLL patients. In addition, there was an upregulation of activating FcγR in monocytes and a subsequent increase in antibody-mediated phagocytosis. This effect required the NF-κB and p38 signaling pathways. Treatment with L18-MDP plus anti-CD20 antibody in the Eµ-TCL model of CLL led to a significant reduction of CLL load, as well as to phenotypic changes in splenic monocytes and macrophages.
CONCLUSIONS
Taken together, these results suggest that NOD2 agonists help overturn the suppression of myeloid cells, and may improve the efficacy of antibody therapy for CLL.
Topics: Nod2 Signaling Adaptor Protein; Animals; Humans; Receptors, IgG; Mice; Macrophages; Leukemia, Lymphocytic, Chronic, B-Cell; Acetylmuramyl-Alanyl-Isoglutamine; Female; Mice, Inbred C57BL; Signal Transduction; Phagocytosis; Rituximab
PubMed: 38919608
DOI: 10.3389/fimmu.2024.1409333 -
BMC Veterinary Research Jun 2024Equine asthma (EA) is a chronic lower airway inflammation that leads to structural and functional changes. Hyaluronic acid (HA) has crucial functions in the...
BACKGROUND
Equine asthma (EA) is a chronic lower airway inflammation that leads to structural and functional changes. Hyaluronic acid (HA) has crucial functions in the extracellular matrix homeostasis and inflammatory mediator activity. HA concentration in the lungs increases in several human airway diseases. However, its associations with naturally occurring EA and airway remodelling have not been previously studied. Our aim was to investigate the association of equine neutrophilic airway inflammation (NAI) severity, airway remodelling, and HA concentration in horses with naturally occurring EA. We hypothesised that HA concentration and airway remodelling would increase with the severity of NAI. HA concentrations of bronchoalveolar lavage fluid supernatant (SUP) and plasma of 27 neutrophilic EA horses, and 28 control horses were measured. Additionally, remodelling and HA staining intensity were assessed from endobronchial biopsies from 10 moderate NAI horses, 5 severe NAI horses, and 15 control horses.
RESULTS
The HA concentration in SUP was higher in EA horses compared to controls (p = 0.007). Plasma HA concentrations were not different between the groups. In the endobronchial biopsies, moderate NAI horses showed epithelial hyperplasia and inflammatory cell infiltrate, while severe NAI horses also showed fibrosis and desquamation of the epithelium. The degree of remodelling was higher in severe NAI compared to moderate NAI (p = 0.048) and controls (p = 0.016). Intense HA staining was observed in bronchial cell membranes, basement membranes, and connective tissue without significant differences between the groups.
CONCLUSION
The release of HA to the airway lumen increases in naturally occurring neutrophilic EA without clear changes in its tissue distribution, and significant airway remodelling only develops in severe NAI.
Topics: Animals; Horses; Hyaluronic Acid; Asthma; Horse Diseases; Airway Remodeling; Bronchoalveolar Lavage Fluid; Female; Male; Neutrophils; Inflammation; Severity of Illness Index
PubMed: 38918797
DOI: 10.1186/s12917-024-04136-2 -
Journal of Neuroinflammation Jun 2024The SARS-CoV-2 virus activates maternal and placental immune responses. Such activation in the setting of other infections during pregnancy is known to impact fetal...
BACKGROUND
The SARS-CoV-2 virus activates maternal and placental immune responses. Such activation in the setting of other infections during pregnancy is known to impact fetal brain development. The effects of maternal immune activation on neurodevelopment are mediated at least in part by fetal brain microglia. However, microglia are inaccessible for direct analysis, and there are no validated non-invasive surrogate models to evaluate in utero microglial priming and function. We have previously demonstrated shared transcriptional programs between microglia and Hofbauer cells (HBCs, or fetal placental macrophages) in mouse models.
METHODS AND RESULTS
We assessed the impact of maternal SARS-CoV-2 on HBCs isolated from 24 term placentas (N = 10 SARS-CoV-2 positive cases, 14 negative controls). Using single-cell RNA-sequencing, we demonstrated that HBC subpopulations exhibit distinct cellular programs, with specific subpopulations differentially impacted by SARS-CoV-2. Assessment of differentially expressed genes implied impaired phagocytosis, a key function of both HBCs and microglia, in some subclusters. Leveraging previously validated models of microglial synaptic pruning, we showed that HBCs isolated from placentas of SARS-CoV-2 positive pregnancies can be transdifferentiated into microglia-like cells (HBC-iMGs), with impaired synaptic pruning behavior compared to HBC models from negative controls.
CONCLUSION
These findings suggest that HBCs isolated at birth can be used to create personalized cellular models of offspring microglial programming.
Topics: Female; Pregnancy; Microglia; Humans; Placenta; COVID-19; Macrophages; Pregnancy Complications, Infectious; SARS-CoV-2; Fetus; Adult; Brain; Mice; Animals
PubMed: 38918792
DOI: 10.1186/s12974-024-03157-w -
Asian Pacific Journal of Cancer... Jun 2024Presently, ovarian cancer remains the leading cause of death in gynecological malignancies. The survival rate of these patients is low, which might be caused by early... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Presently, ovarian cancer remains the leading cause of death in gynecological malignancies. The survival rate of these patients is low, which might be caused by early metastases and delayed diagnosis. Therefore, it is crucial to investigate novel practical markers that provide early prognostic value which helps construct individualized treatment.
METHODS
A thorough investigation of the neutrophil-lymphocyte ratio (NLR) and lymphocyte ratio (PLR) in ovarian cancer patients was conducted using article selection from PubMed, Cochrane, Science Direct, and Google Scholar databases. The outcomes and hazard ratio (HR) were obtained using Review Manager 5.4, and the 95% Confidence Interval (CI) result was calculated. The chief endpoints of interest in this study include overall survival (OS) and progression-free survival (PFS).
RESULTS
Sixteen studies with 3,862 patients were included with a mean age of 50.6 years and a mean follow-up of 45.84 months. Multivariate studies demonstrated that a higher NLR is associated with worse PFS and OS, HR 1.35;95% CI [1.05-1.74] and HR 1.46; 95% CI [1.16-1.83] respectively. Similar results are observed with PLR and poorer PFS and OS, HR 1.62; 95% CI [1.09-2.43] and HR 1.66; 95% CI [1.12-2.46].
CONCLUSION
Pre-treatment PLR and NLR were found to be prognostic factors in determining PFS and OS in ovarian cancer. High values in pre-treatment PLR and NLR may indicate worse clinical outcomes.
Topics: Humans; Female; Ovarian Neoplasms; Neutrophils; Prognosis; Lymphocytes; Biomarkers, Tumor; Blood Platelets; Lymphocyte Count; Survival Rate; Platelet Count
PubMed: 38918652
DOI: 10.31557/APJCP.2024.25.6.1921 -
Nature Communications Jun 2024Adipose tissue macrophages (ATMs) influence obesity-associated metabolic dysfunction, but the mechanisms by which they do so are not well understood. We show that...
Adipose tissue macrophages (ATMs) influence obesity-associated metabolic dysfunction, but the mechanisms by which they do so are not well understood. We show that miR-6236 is a bona fide miRNA that is secreted by ATMs during obesity. Global or myeloid cell-specific deletion of miR-6236 aggravates obesity-associated adipose tissue insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. miR-6236 augments adipocyte insulin sensitivity by inhibiting translation of negative regulators of insulin signaling, including PTEN. The human genome harbors a miR-6236 homolog that is highly expressed in the serum and adipose tissue of obese people. hsa-MIR-6236 expression negatively correlates with hyperglycemia and glucose intolerance, and positively correlates with insulin sensitivity. Together, our findings establish miR-6236 as an ATM-secreted miRNA that potentiates adipocyte insulin signaling and protects against metabolic dysfunction during obesity.
Topics: MicroRNAs; Obesity; Animals; Adipocytes; Hyperglycemia; Humans; Signal Transduction; Insulin; Insulin Resistance; Mice; Male; PTEN Phosphohydrolase; Mice, Inbred C57BL; Macrophages; Adipose Tissue; Myeloid Cells; Mice, Knockout; Hyperinsulinism
PubMed: 38918428
DOI: 10.1038/s41467-024-49632-z -
Signal Transduction and Targeted Therapy Jun 2024
Topics: Tuberculosis; Macrophages; Humans; Nanoparticles; Cell Membrane; Animals; Mycobacterium tuberculosis; Macrophage Activation; Mice
PubMed: 38918362
DOI: 10.1038/s41392-024-01855-8 -
PloS One 2024The Neutrophil-to-Lymphocyte Ratio (NLR) is a clinical indicator of peripheral inflammation that is easily accessible. It is worth noting that the formation of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The Neutrophil-to-Lymphocyte Ratio (NLR) is a clinical indicator of peripheral inflammation that is easily accessible. It is worth noting that the formation of amyloid-β (Aβ) plaques and neurofibrillary tangles has been linked to inflammation and immune dysregulation. The main objective of this systematic review and meta-analysis is to comprehensively evaluate the existing body of research concerning the NLR in the context of Alzheimer's disease (AD) and mild cognitive impairment (MCI).
METHOD
We conducted a comprehensive online search and included studies that evaluated the NLR in 1) patients with AD or MCI and 2) healthy control (HC) participants. We also pooled mean and standard deviation (SD) data for each group.
RESULTS
Ultimately, 12 studies encompassed 1,309 individuals diagnosed with AD with mean NLR levels of 2.68, 1,929 individuals with MCI with mean NLR levels of 2.42, and 2,064 HC with mean NLR levels of 2.06 were included in this systematic review and meta-analysis. The mean NLR was 0.59 higher in AD patients compared to HC participants (mean difference (MD) = 0.59 [0.38; 0.80]). Similarly, the mean NLR was higher in AD than MCI patients (MD = 0.23 [0.13; 0.33]). Additionally, the mean NLR was higher in individuals with MCI compared to HC participants (MD = 0.37 [0.22; 0.52]). In the subgroup meta-analysis based on the Mini-Mental State Examination (MMSE), AD patients with lower MMSE scores (using a cut-off of 20) exhibited significantly higher mean NLR (3.10 vs. 2.70, with a p-value for subgroup differences < 0.01).
CONCLUSION
The NLR, which serves as a marker of peripheral inflammation, shows increased levels in individuals with AD and MCI compared to HC participants. Furthermore, our study indicates that NLR levels are significantly higher in AD than MCI. Additionally, our novel finding suggests significantly higher NLR levels among AD patients with more severe cognitive decline compared to AD patients with less severe cognitive decline. So, it can be concluded that the higher cognitive decline in humans is accompanied by higher NLR levels. Further longitudinal researches are needed to explore more details about the relationship between inflammation and dementia.
Topics: Alzheimer Disease; Humans; Neutrophils; Lymphocytes; Cognitive Dysfunction; Lymphocyte Count
PubMed: 38917167
DOI: 10.1371/journal.pone.0305322 -
ImmunoHorizons Jun 2024Malaria is a serious vector-borne disease characterized by periodic episodes of high fever and strong immune responses that are coordinated with the daily synchronized...
Malaria is a serious vector-borne disease characterized by periodic episodes of high fever and strong immune responses that are coordinated with the daily synchronized parasite replication cycle inside RBCs. As immune cells harbor an autonomous circadian clock that controls various aspects of the immune response, we sought to determine whether the intensity of the immune response to Plasmodium spp., the parasite causing malaria, depends on time of infection. To do this, we developed a culture model in which mouse bone marrow-derived macrophages are stimulated with RBCs infected with Plasmodium berghei ANKA (iRBCs). Lysed iRBCs, but not intact iRBCs or uninfected RBCs, triggered an inflammatory immune response in bone marrow-derived macrophages. By stimulating at four different circadian time points (16, 22, 28, or 34 h postsynchronization of the cells' clock), 24-h rhythms in reactive oxygen species and cytokines/chemokines were found. Furthermore, the analysis of the macrophage proteome and phosphoproteome revealed global changes in response to iRBCs that varied according to circadian time. This included many proteins and signaling pathways known to be involved in the response to Plasmodium infection. In summary, our findings show that the circadian clock within macrophages determines the magnitude of the inflammatory response upon stimulation with ruptured iRBCs, along with changes of the cell proteome and phosphoproteome.
Topics: Animals; Macrophages; Mice; Erythrocytes; Malaria; Plasmodium berghei; Circadian Rhythm; Mice, Inbred C57BL; Reactive Oxygen Species; Cytokines; Circadian Clocks; Cells, Cultured; Proteome
PubMed: 38916585
DOI: 10.4049/immunohorizons.2400021 -
The ISME Journal Jun 2024As unicellular predators, ciliates engage in close associations with diverse microbes, laying the foundation for the establishment of endosymbiosis. Originally...
As unicellular predators, ciliates engage in close associations with diverse microbes, laying the foundation for the establishment of endosymbiosis. Originally heterotrophic, ciliates demonstrate the ability to acquire phototrophy by phagocytizing unicellular algae or by sequestering algal plastids. This adaptation enables them to gain photosynthate and develop resistance to unfavorable environmental conditions. The integration of acquired phototrophy with intrinsic phagotrophy results in a trophic mode known as mixotrophy. Additionally, ciliates can harbor thousands of bacteria in various intracellular regions, including the cytoplasm and nucleus, exhibiting species specificity. Under prolonged and specific selective pressure within hosts, bacterial endosymbionts evolve unique lifestyles and undergo particular reductions in metabolic activities. Investigating the research advancements in various endosymbiotic cases within ciliates will contribute to elucidate patterns in cellular interaction and unravel the evolutionary origins of complex traits.
PubMed: 38916437
DOI: 10.1093/ismejo/wrae117 -
Microbiology (Reading, England) Jun 2024Bacterial infection is a dynamic process resulting in a heterogenous population of infected and uninfected cells. These cells respond differently based on their...
Bacterial infection is a dynamic process resulting in a heterogenous population of infected and uninfected cells. These cells respond differently based on their bacterial load and duration of infection. In the case of infection of macrophages with Crohn's disease (CD) associated adherent-invasive (AIEC), understanding the drivers of pathogen success may allow targeting of cells where AIEC replicate to high levels. Here we show that stratifying immune cells based on their bacterial load identifies novel pathways and therapeutic targets not previously associated with AIEC when using a traditional homogeneous infected population approach. Using flow cytometry-based cell sorting we stratified cells into those with low or high intracellular pathogen loads, or those which were bystanders to infection. Immune cells transcriptomics revealed a diverse response to the varying levels of infection while pathway analysis identified novel intervention targets that were directly related to increasing intracellular AIEC numbers. Chemical inhibition of identified targets reduced AIEC intracellular replication or inhibited secretion of tumour necrosis factor alpha (TNFα), a key cytokine associated with AIEC infection. Our results have identified new avenues of intervention in AIEC infection that may also be applicable to CD through the repurposing of already available inhibitors. Additionally, they highlight the applicability of immune cell stratification post-infection as an effective approach for the study of microbial pathogens.
Topics: Crohn Disease; Macrophages; Humans; Escherichia coli Infections; Escherichia coli; Tumor Necrosis Factor-alpha; Bacterial Load; Bacterial Adhesion; Host-Pathogen Interactions
PubMed: 38916198
DOI: 10.1099/mic.0.001470