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Life Science Alliance Sep 2024Genome-wide association studies have identified over 200 genetic loci associated with inflammatory bowel disease; however, the mechanism of such a large amount of...
Genome-wide association studies have identified over 200 genetic loci associated with inflammatory bowel disease; however, the mechanism of such a large amount of susceptibility genes remains uncertain. In this study, we integrated bioinformatics analysis and two independent single-cell transcriptome datasets to investigate the expression network of 232 susceptibility genes in Crohn's disease (CD) patients and healthy controls. The study revealed that most of the susceptibility genes are specifically and strictly expressed in the monocytes of the human intestinal tract. The susceptibility genes established a network within the monocytes of health control. The robustness of a gene network may prevent disease onset that is influenced by the genetic and environmental alteration in the expression of susceptibility genes. In contrast, we showed a sparse network in pediatric/adult CD patients, suggesting the broken network contributed to the CD etiology. The network status of susceptibility genes at the single-cell level of monocytes provided novel insight into the etiology.
Topics: Crohn Disease; Humans; Monocytes; Genetic Predisposition to Disease; Gene Regulatory Networks; Genome-Wide Association Study; Computational Biology; Adult; Gene Expression Profiling; Transcriptome; Child; Case-Control Studies; Single-Cell Analysis; Polymorphism, Single Nucleotide; Male; Female
PubMed: 38925865
DOI: 10.26508/lsa.202302394 -
Science Advances Jun 2024There is a regional preference around lymph nodes (LNs) for adipose beiging. Here, we show that local LN removal within inguinal white adipose tissue (iWAT) greatly...
There is a regional preference around lymph nodes (LNs) for adipose beiging. Here, we show that local LN removal within inguinal white adipose tissue (iWAT) greatly impairs cold-induced beiging, and this impairment can be restored by injecting M2 macrophages or macrophage-derived C-C motif chemokine (CCL22) into iWAT. CCL22 injection into iWAT effectively promotes iWAT beiging, while blocking CCL22 with antibodies can prevent it. Mechanistically, the CCL22 receptor, C-C motif chemokine receptor 4 (CCR4), within eosinophils and its downstream focal adhesion kinase/p65/interleukin-4 signaling are essential for CCL22-mediated beige adipocyte formation. Moreover, CCL22 levels are inversely correlated with body weight and fat mass in mice and humans. Acute elevation of CCL22 levels effectively prevents diet-induced body weight and fat gain by enhancing adipose beiging. Together, our data identify the CCL22-CCR4 axis as an essential mediator for LN-controlled adaptive thermogenesis and highlight its potential to combat obesity and its associated complications.
Topics: Thermogenesis; Chemokine CCL22; Animals; Macrophages; Energy Metabolism; Mice; Humans; Lymph Nodes; Adipose Tissue, White; Male; Receptors, CCR4; Obesity; Signal Transduction; Mice, Inbred C57BL; Eosinophils; Female; Adipocytes, Beige
PubMed: 38924414
DOI: 10.1126/sciadv.adn5229 -
Proceedings of the National Academy of... Jul 2024The non-neural cholinergic system plays a critical role in regulating immune equilibrium and tissue homeostasis. While the expression of choline acetyltransferase...
The non-neural cholinergic system plays a critical role in regulating immune equilibrium and tissue homeostasis. While the expression of choline acetyltransferase (ChAT), the enzyme catalyzing acetylcholine biosynthesis, has been well documented in lymphocytes, its role in the myeloid compartment is less understood. Here, we identify a significant population of macrophages (Mϕs) expressing ChAT and synthesizing acetylcholine in the resolution phase of acute peritonitis. Using -GFP reporter mice, we observed marked upregulation of ChAT in monocyte-derived small peritoneal Mϕs (SmPMs) in response to Toll-like receptor agonists and bacterial infections. These SmPMs, phenotypically and transcriptionally distinct from tissue-resident large peritoneal macrophages, up-regulated ChAT expression through a MyD88-dependent pathway involving MAPK signaling. Notably, this process was attenuated by the TRIF-dependent TLR signaling pathway, and our tests with a range of neurotransmitters and cytokines failed to induce a similar response. Functionally, deficiency in Mϕs led to significantly decreased peritoneal acetylcholine levels, reduced efferocytosis of apoptotic neutrophils, and a delayed resolution of peritonitis, which were reversible with exogenous ACh supplementation. Intriguingly, despite B lymphocytes being a notable ChAT-expressing population within the peritoneal cavity, deletion in B cells did not significantly alter the resolution process. Collectively, these findings underscore the crucial role of Mϕ-derived acetylcholine in the resolution of inflammation and highlight the importance of the non-neuronal cholinergic system in immune regulation.
Topics: Animals; Choline O-Acetyltransferase; Peritonitis; Mice; Macrophages, Peritoneal; Acetylcholine; Myeloid Differentiation Factor 88; Mice, Inbred C57BL; Signal Transduction; Inflammation; B-Lymphocytes; Toll-Like Receptors; Phagocytosis; Macrophages; Mice, Knockout
PubMed: 38923993
DOI: 10.1073/pnas.2402143121 -
Immunity, Inflammation and Disease Jun 2024The ongoing outbreak of the respiratory disease coronavirus disease 2019 (COVID-19) is currently presenting a major global health threat. This pandemic is unprecedented...
OBJECTIVE
The ongoing outbreak of the respiratory disease coronavirus disease 2019 (COVID-19) is currently presenting a major global health threat. This pandemic is unprecedented in recent human history. The objective of this study was to examine the relationship between cycle quantitation (Cq) and laboratory parameters in COVID-19 patients, aiming to determine if Cq levels can provide valuable insights into the COVID-19 disease.
METHODS
This study involved 234 participants who were divided into case and control groups. Real-time PCR tests were used to diagnose COVID-19 cases in the study participants. Blood tests, including complete blood count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), D-dimer, IgG, and IgM, were also conducted. Statistical analysis was performed using SPSS 22 software.
RESULTS
The findings showed that COVID-19-positive cases had significantly higher levels of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), D-dimer, ESR, CRP, and LDH compared to normal cases. Additionally, the case group had significantly lower lymphocyte and platelet counts. There was a statistically significant positive correlation between Cq levels and lymphocyte count (r = .124, p = .014). Conversely, there was a statistically significant inverse correlation between Cq levels and NLR (r = -.208, p = .017). Furthermore, the evaluation of hematological, inflammatory, and biochemical indexes in COVID-19 patients using the receiver-operating characteristics curve demonstrated statistically appropriate sensitivity and specificity.
CONCLUSION
Our outcomes indicated a significant association between Cq levels and PLR, NLR, D-dimer, CRP, and ESR in COVID-19 patients. Consequently, including the report of laboratory parameters alongside Cq values offers a promising prognosis.
Topics: Humans; COVID-19; Male; Female; Middle Aged; SARS-CoV-2; Adult; C-Reactive Protein; Fibrin Fibrinogen Degradation Products; Blood Sedimentation; Aged; Neutrophils; Platelet Count; L-Lactate Dehydrogenase; Case-Control Studies; Lymphocytes
PubMed: 38923849
DOI: 10.1002/iid3.1326 -
ELife Jun 2024During tuberculosis (TB), migration of dendritic cells (DCs) from the site of infection to the draining lymph nodes is known to be impaired, hindering the rapid...
During tuberculosis (TB), migration of dendritic cells (DCs) from the site of infection to the draining lymph nodes is known to be impaired, hindering the rapid development of protective T-cell-mediated immunity. However, the mechanisms involved in the delayed migration of DCs during TB are still poorly defined. Here, we found that infection of DCs with (Mtb) triggers HIF1A-mediated aerobic glycolysis in a TLR2-dependent manner, and that this metabolic profile is essential for DC migration. In particular, the lactate dehydrogenase inhibitor oxamate and the HIF1A inhibitor PX-478 abrogated Mtb-induced DC migration in vitro to the lymphoid tissue-specific chemokine CCL21, and in vivo to lymph nodes in mice. Strikingly, we found that although monocytes from TB patients are inherently biased toward glycolysis metabolism, they differentiate into poorly glycolytic and poorly migratory DCs compared with healthy subjects. Taken together, these data suggest that because of their preexisting glycolytic state, circulating monocytes from TB patients are refractory to differentiation into migratory DCs, which may explain the delayed migration of these cells during the disease and opens avenues for host-directed therapies for TB.
Topics: Dendritic Cells; Glycolysis; Monocytes; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mycobacterium tuberculosis; Cell Movement; Animals; Tuberculosis; Mice; Toll-Like Receptor 2; Mice, Inbred C57BL; Female
PubMed: 38922679
DOI: 10.7554/eLife.89319 -
Anais Da Academia Brasileira de Ciencias 2024The tumor microenvironment (TME) harbors several cell types, such as tumor cells, immune cells, and non-immune cells. These cells communicate through several mechanisms,... (Review)
Review
The tumor microenvironment (TME) harbors several cell types, such as tumor cells, immune cells, and non-immune cells. These cells communicate through several mechanisms, such as cell-cell contact, cytokines, chemokines, and extracellular vesicles (EVs). Tumor-derived vesicles are known to have the ability to modulate the immune response. Monocytes are a subset of circulating innate immune cells and play a crucial role in immune surveillance, being recruited to tissues where they differentiate into macrophages. In the context of tumors, it has been observed that tumor cells can attract monocytes to the TME and induce their differentiation into tumor-associated macrophages with a pro-tumor phenotype. Tumor-derived EVs have emerged as essential structures mediating this process. Through the transfer of specific molecules and signaling factors, tumor-derived EVs can shape the phenotype and function of monocytes, inducing the expression of cytokines and molecules by these cells, thus modulating the TME towards an immunosuppressive environment.
Topics: Extracellular Vesicles; Humans; Monocytes; Tumor Microenvironment; Neoplasms; Macrophages; Cytokines; Cell Differentiation
PubMed: 38922279
DOI: 10.1590/0001-3765202420231212 -
Toxins May 2024Cardiovascular disease (CVD) frequently occurs in patients with chronic kidney disease (CKD), particularly those undergoing dialysis. The mechanisms behind this may be... (Review)
Review
Cardiovascular disease (CVD) frequently occurs in patients with chronic kidney disease (CKD), particularly those undergoing dialysis. The mechanisms behind this may be related to traditional risk factors and CKD-specific factors that accelerate atherosclerosis and vascular calcification in CKD patients. The accumulation of uremic toxins is a significant factor in CKD-related systemic disorders. Basic research suggests that indoxyl sulfate (IS), a small protein-bound uremic toxin, is associated with macrophage dysfunctions, including increased oxidative stress, exacerbation of chronic inflammation, and abnormalities in lipid metabolism. Strategies to mitigate the toxicity of IS include optimizing gut microbiota, intervening against the abnormality of intracellular signal transduction, and using blood purification therapy with higher efficiency. Further research is needed to examine whether lowering protein-bound uremic toxins through intervention leads to a reduction in CVD in patients with CKD.
Topics: Indican; Humans; Atherosclerosis; Macrophages; Animals; Uremia; Renal Insufficiency, Chronic; Uremic Toxins; Gastrointestinal Microbiome; Oxidative Stress
PubMed: 38922148
DOI: 10.3390/toxins16060254 -
Veterinary Sciences Jun 2024Traditionally, non- staphylococci and mammaliicocci (NASM) were not considered significant players in bovine mastitis. This study investigated the involvement of NASM (...
Traditionally, non- staphylococci and mammaliicocci (NASM) were not considered significant players in bovine mastitis. This study investigated the involvement of NASM ( and ) and lactic acid bacteria (LAB) strains () through bovine neutrophil responses. Bovine neutrophils displayed minimal apoptosis upon NASM and LAB challenge. Neutrophils expressed high TLR2 after challenge, but TLR6 expression varied and remained low in NASM pathogen recognition. Bovine neutrophils effectively engulfed and killed LAB, but their activity was significantly impaired against NASM. This was evident in , where reduced TLR6 recognition and a weakened phagocytic response likely contributed to a lower bactericidal effect. Regardless of the bacteria encountered, intracellular ROS production remained high. -challenged neutrophils displayed upregulation in genes for pathogen recognition (TLRs), ROS production, and both pro- and anti-apoptotic pathways. This response mirrored that of . except for and , suggesting these bacteria have divergent roles in triggering cell death. Our findings suggest that manipulates bovine neutrophil defenses through coordinated changes in functional responses and gene expression, while LAB strains have a weaker influence on apoptosis.
PubMed: 38922009
DOI: 10.3390/vetsci11060262 -
Pathogens (Basel, Switzerland) May 2024Coronavirus frequently infects humans and animals, showing the ability to recombine and cross over to different species. Cats can be considered a model for studying...
Coronavirus frequently infects humans and animals, showing the ability to recombine and cross over to different species. Cats can be considered a model for studying coronavirus infection, in which feline coronavirus (FCoV) represents a major enteric pathogen related to gastroenteric disease. In this animal, the virus can acquire tropism for macrophage cells, leading to a deadly disease called feline infectious peritonitis (FIP). In this study, monocyte-derived macrophages were isolated by CD14-positive selection in venous whole blood from 26 cats with FIP and 32 FCoV-positive healthy cats. Phagocytosis and respiratory burst activities were investigated and compared between the groups. This is the first study comparing macrophage activity in cats affected by FIP and healthy cats positive for FCoV infection. Our results showed that in cats with FIP, the phagocytic and respiratory burst activities were significantly lower. Our results support the possible role of host immunity in Coronaviridae pathogenesis in cats, supporting future research on the immune defense against this systemic disease.
PubMed: 38921735
DOI: 10.3390/pathogens13060437 -
Marine Drugs Jun 2024SeviL, a galactoside-binding lectin previously isolated from the mussel , was demonstrated to trigger apoptosis in HeLa ovarian cancer cells. Here, we show that this...
SeviL, a galactoside-binding lectin previously isolated from the mussel , was demonstrated to trigger apoptosis in HeLa ovarian cancer cells. Here, we show that this lectin can promote the polarization of macrophage cell lines toward an M1 functional phenotype at low concentrations. The administration of SeviL to monocyte and basophil cell lines reduced their growth in a dose-dependent manner. However, low lectin concentrations induced proliferation in the RAW264.7 macrophage cell line, which was supported by the significant up-regulation of TOM22, a component of the mitochondrial outer membrane. Furthermore, the morphology of lectin-treated macrophage cells markedly changed, shifting from a spherical to an elongated shape. The ability of SeviL to induce the polarization of RAW264.7 cells to M1 macrophages at low concentrations is supported by the secretion of proinflammatory cytokines and chemokines, as well as by the enhancement in the expression of IL-6- and TNF-α-encoding mRNAs, both of which encode inflammatory molecular markers. Moreover, we also observed a number of accessory molecular alterations, such as the activation of MAP kinases and the JAK/STAT pathway and the phosphorylation of platelet-derived growth factor receptor-α, which altogether support the functional reprogramming of RAW264.7 following SeviL treatment. These results indicate that this mussel β-trefoil lectin has a concentration-dependent multifunctional role in regulating cell proliferation, phenotype, and death in macrophages, suggesting its possible involvement in regulating hemocyte activity in vivo.
Topics: Animals; Mice; Macrophages; RAW 264.7 Cells; Lectins; Bivalvia; Cell Proliferation; Humans; Cytokines; Phenotype; Signal Transduction
PubMed: 38921580
DOI: 10.3390/md22060269