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Macrophage infiltration and accumulation in the atherosclerotic lesion are associated with plaque progression and instability. Depletion of macrophages from the lesion might provide valuable insights into plaque stabilization processes. Therefore, we assessed the effects of systemic and local macrophage depletion on atherogenesis. To deplete monocytes/macrophages we used atherosclerosis‐susceptible Apoe−/− mice, bearing a MaFIA (macrophage‐Fas‐induced‐apoptosis) suicide construct under control of the Csf1r (CD115) promotor, where selective apoptosis of Csf1r‐expressing cells was induced in a controlled manner, by administration of a drug, AP20187. Systemic induction of apoptosis resulted in a decrease in lesion macrophages and smooth‐muscle cells. Plaque size and necrotic core size remained unaffected. Two weeks after the systemic depletion of macrophages, we observed a replenishment of the myeloid compartment. Myelopoiesis was modulated resulting in an expansion of CSF1Rlo myeloid cells in the circulation and a shift from Ly6chi monocytes toward Ly6cint and Ly6clo populations in the spleen. Local apoptosis induction led to a decrease in plaque burden and macrophage content with marginal effects on the circulating myeloid cells. Local, but not systemic depletion of Csf1r+ myeloid cells resulted in decreased plaque burden. Systemic depletion led to CSF1Rlo‐monocyte expansion in blood, possibly explaining the lack of effects on plaque development. [ABSTRACT FROM AUTHOR]

Acinetobacter baumannii is an opportunistic Gram‐negative bacterium representing one of the leading causes of ventilator‐associated pneumonia. The development of pneumonia results from a complex interplay between pathogens and pulmonary innate mucosal immunity. Therefore, the knowledge of the host immune responses is pivotal for the development of effective therapeutics to treat A. baumannii infections. Previous studies were conducted using cell lines and animal models, but a comprehensive understanding of the interaction between A. baumannii and primary human immune cells is still lacking. To bridge this gap, we investigated the response of primary monocytes, macrophages, and dendritic cells to the A. baumannii‐type strain and an epidemic clinical isolate. We found that all immune cells trigger different responses when interacting with A. baumannii. In particular, macrophages and monocytes mediate bacterial clearance, whereas monocytes and dendritic cells activate a late response through the production of cytokines, chemokines, and the expression of co‐stimulatory molecules. The epidemic strain induces lower expression of interleukin‐10 and CD80 compared with the type strain, potentially constituting two immune evasion strategies. [ABSTRACT FROM AUTHOR]

Background: This study explores the significance of computed tomography (CT) radiomic features, along with inflammation and nutrition biomarkers, in the prognosis of postoperative patients with T3N0M0 esophageal squamous cell carcinoma (ESCC). The study aims to construct a related nomogram. Methods: A total of 114 patients were enrolled and randomly assigned to training and validation cohorts in a 7:3 ratio. Radiomic features were extracted from their preoperative chest‐enhanced CT arterial images of the primary tumor, and inflammatory and nutritional indices, including neutrophil‐to‐lymphocyte ratio (NLR), lymphocyte‐to‐monocyte ratio (LMR), platelet‐to‐lymphocyte ratio (PLR), systemic immune‐inflammation index (SII), and prognostic nutritional index (PNI), were calculated based on laboratory data from the 3 days before surgery. Intra‐class correlations coefficient (ICC) and least absolute shrinkage and selection operator (Lasso) were applied to screen valuable radiomics features predicting overall survival (OS), and the Rad‐score was calculated. In the training cohort, univariate and multivariate Cox regression analyses identified independent prognostic factors, which were adopted to establish the nomogram. Results: Eight radiomic features were selected for Rad‐score calculation. Multivariate Cox regression revealed Rad‐score, PNI, NLR, and PLR as independent prognostic factors for ESCC patients (p < 0.05). A nomogram was constructed based on these variables. The concordance index (C‐index) for the nomogram was 0.797 (95% CI: 0.726–0.868) in the training cohort and 0.796 (95% CI: 0.702–0.890) in the validation cohort. Calibration curves indicated good calibration ability, and the receiver operating characteristic (ROC) analysis demonstrated superior discriminative ability for the nomogram in comparison to the Rad‐score alone. Decision curve analysis (DCA) confirmed the clinical utility of the nomogram. Conclusion: We developed and validated a nomogram for predicting the OS of postoperative T3N0M0 ESCC patients, integrating nutritional, inflammatory markers, and radiomic signature. The combined nomogram can serve as a robust tool for risk stratification and clinical management. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Methods Results Conclusions Estimating patient risk before heart surgery (HS) is crucial. Perioperative inflammation is associated with several complications and mortality. This study investigated blood cell count inflammatory indices (BCCII) to predict risks, including neutrophil‐to‐lymphocyte ratio (NLR), derivate NLR (DNLR), neutrophil‐to‐platelet‐lymphocyte ratio (NLPR), lymphocyte‐to‐monocyte ratio, platelet‐to‐lymphocyte ratio (PLR), Systemic Inflammatory Index (SII), Systemic Inflammatory Reaction Index (SIRI), and Aggregate Index of Systemic Inflammation (AISI).Data from a cohort of patients undergoing on‐pump HS at a single center in Brazil were retrospectively analyzed. Data were obtained from medical records and a laboratory analyzer, and SPSS version 20.0 was used for index calculations and statistical analyses.In total, 444 surgeries were performed, and 40 in‐hospital deaths occurred. Except for PLR, all other indexes were independent predictors of death after multivariate adjustment (all p < 0.05). Discrimination performance was absent for PLR and AISI, and NLR, NLPR, and DNLR demonstrated the best area under the receiver operating characteristic curve (AUC > 0.7; all p < 0.0001). For survivors (n = 404), all indexes exhibited a correlation with the length of hospital stay (all p < 0.03), and NLR, NLPR, and DNLR were predictors (p < 0.026) of poor operative outcomes (acute myocardial infarction, cerebrovascular attack, cardiac arrest, low cardiac output, prolonged mechanical ventilation, renal failure, and sepsis).All BCCII scores were associated with length of hospital stay. Apart from PLR, all indexes were independent predictors of in‐hospital mortality. Accuracy was highest for NLR, NLPR, and DNLR; for survivors, these three factors were good predictors of poor operative outcomes. [ABSTRACT FROM AUTHOR]

Persistent inflammation, characterized by the intense interplay of inflammatory chemokine secretion and immune cell infiltration, is a hallmark of many skin disorders including diabetic wounds and psoriasis with inadequate therapeutic interventions. Monocyte chemotactic protein‐1 (MCP‐1) is an inflammatory chemokine that plays a key role in recruiting and polarizing monocytes into pro‐inflammatory macrophages to establish a vicious cycle that worsens the inflamed tissue microenvironment. Here, the sponge‐like microneedles (HPMN) technology is described to alleviate inflammatory skin disorders. Heparin/4‐arm PEG‐NH2 network crosslinked onto microneedle surface spatially attracted and sequestered multiple inflammatory chemokines including MCP‐1. Enrichment of MCP‐1 on microneedles recruits and traps inflammatory monocytes within the porous structure of microneedles. Subsequent removal of microneedles not only depletes inflammatory chemokine, MCP‐1, but also its cellular source. As a result, HPMN treatment facilitates 47.1% smaller open wound area in mice and 27.2% shorter wound length in pigs. To demonstrate the versatility of the HPMN technology, it is also shown that combining the method with standard‐of‐care immunosuppressants reduces 45.1% epidermis thickening and attenuated immune cell influx in a mouse psoriasis model. Overall, the HPMN technology is a novel demonstration of employing inflammatory chemokine and cell extraction to treat a broad range of inflammatory skin disorders. [ABSTRACT FROM AUTHOR]

Background: The nerve growth factor (NGF) has been previously shown to be involved in cellular proliferation, differentiation, survival, or wound healing. This factor displays a variety of biological effects that yet remain to be explored. Previous data on cell lines show a pro‐inflammatory role of NGF on monocytes. Objectives: The objective of the study was to investigate the pro‐inflammatory effect of NGF, using a model of fresh human monocytes. Methods: Monocytes obtained from PBMC were exposed to NGF at various concentrations. Alternatively, monocytes were exposed to BSA, the NGF carrier protein without the NGF. Gene expression and cytokine release in the supernatant were monitored. Results: We found that NGF increased the expression of pro‐inflammatory, chemotactic, and remodeling genes such as interleukin (IL)‐1β, IL‐6, tumor necrosis factor (TNF)‐α, and C‐X‐C motif ligand (CXCL)8. The protein levels of CXCL8 and matrix metalloproteinase (MMP)‐9 were also increased in the cell supernatants following NGF exposure. BSA alone was found to drive part of this response, bringing nuance to the inflammatory potential of the NGF. Conclusion: These data suggest that NGF is able to enhance monocyte inflammatory responses once cells are stimulated with another signal but is possibly not able to directly activate it. This could have implications for example in patients with bacterial infections, where NGF could worsen the local inflammation by over‐activating immune cells. [ABSTRACT FROM AUTHOR]

Stress may play a key role in alopecia areata (AA), though the exact interactions of stress with AA remain undefined. Corticotropin‐releasing hormone (CRH), the proximal regulator of the stress axis, has been recognized as an immunomodulatory factor in tissues and peripheral blood mononuclear cells (PBMCs). We used multicolour flow cytometry to identify receptor CRHR1 expression on PBMC subsets in AA patients (n = 54) and controls (n = 66). We found that CRHR1 was primarily expressed by circulating monocytes. CRHR1 expression on monocytes was enhanced in AA compared with controls (3.17% vs. 1.44%, p = 0.002, chi‐squared test). AA incidence was correlated to elevated CD14+ monocyte numbers (R = 0.092, p = 0.036) and markedly independently correlated with increased CRHR1 expression (R = 0.215, p = 0.027). High CRHR1 expression was significantly related to chronic AA (disease duration >1 year; p = 0.003, chi‐squared test), and large lesion area (AA area >25%; p = 0.049, chi‐squared test). We also observed enhanced percentages of active monocytes and reduced CD16+ CD3− NK cell numbers in AA patients' PBMCs (p = 0.010; 0.025, respectively). In vitro CRH treatment of PBMCs and human monocyte cell line THP‐1 promoted CD86 upregulation. The findings imply that stress‐related factors CRH and CRHR1 contribute to AA development and progression where higher CRHR1 expression is associated with chronic AA and larger lesions. [ABSTRACT FROM AUTHOR]

Background: The monocyte–lymphocyte ratio (MLR) is a hematological test parameter that reflects the status of both monocytes and lymphocytes as inflammatory cells. This study aims to investigate the relationship between MLR and carotid intraplaque neovascularization (IPN) in patients with asymptomatic carotid stenosis. Methods: We performed the Angio Planewave Ultrasensitive (AngioPLUS) screening for patients with carotid plaques. The carotid plaque stability was evaluated by semiquantitative visual grading of carotid IPN. Binary logistic regression models were performed to determine the associations between different clinical and laboratory indicators and the presence of high IPN. Results: A total of 160 patients were eventually enrolled with 99 in the low IPN group (Scores 0–1) and 61 in the high IPN group (Score 2). Univariate logistic regression showed that age, monocytes, lymphocytes, glycated hemoglobin (HbA1c), fibrinogen, d‐dimmer, and MLR were significantly associated with the presence of high IPN (all p < 0.05). Multivariate logistic regression models showed that MLR was significantly associated with the presence of high IPN after adjusting for other covariates. An MLR value of 32.9 was the optimal cutoff value to differentiate high and low IPN. High MLR was also significantly correlated with the presence of high IPN (odds ratio [OR] = 4.08, 95% confidence interval [CI]: 1.69–9.88, p = 0.002) when included in the above multivariate logistic regression model. Conclusion: Elevated MLR is closely associated with the presence of high IPN and may serve as a surrogate biomarker for carotid IPN. [ABSTRACT FROM AUTHOR]

Summary: Oxidative stress in patients suffering from obstructive sleep apnea syndrome (OSAS) is associated with a low‐grade systemic inflammation, immune disturbance, and increased invasion of monocytes into the endothelium. Besides continuous positive airway pressure (PAP), hypoglossal nerve stimulation (HNS) has become a promising treatment option for patients with OSAS. We aimed to analyse the influence of HNS therapy on the cellular characteristics relevant for adhesion and immune regulation of circulating CD14/CD16 monocyte subsets. Whole blood flow cytometric measurements were performed to analyse the expression levels of different adhesion molecules and checkpoint molecule PD‐L1 (programmed death‐ligand 1) in connection with pro‐inflammatory plasma cytokine IL‐8 and the clinical values of BMI (body mass index), AHI (apnea–hypopnea index), ODI (oxygen desaturation index), and ESS (Epworth sleepiness scale) upon HNS treatment. Hypoglossal nerve stimulation treatment significantly improved the expression of adhesion molecule CD162 (P‐selectin receptor) on non‐classical monocytes and significantly downregulated the expression of PD‐L1 on all three monocyte subsets. We conclude that the holistic improvement of different parameters such as the oxygenation of the peripheral blood, a reduced systemic inflammation, and the individual sleeping situation upon HNS respiratory support, leads to an improved immunologic situation. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN), a severe complication of type 2 diabetes mellitus (T2DM), is marked by heightened endoplasmic reticulum stress (ERS) and oxidative stress (OS) due to protein misfolding and free radical generation. We investigated the sodium‐glucose co‐transporter‐2 inhibitor (SGLT2i), canagliflozin (Cana), in alleviating ERS and OS in DN patients and THP‐1 cells under hyperglycemic condition. A total of 120 subjects were divided into four groups, with 30 subjects in each group: healthy controls, T2DM individuals, DN patients receiving standard treatment, and those treated with Cana. The control group had no history of diabetes, cardiovascular or renal diseases, or other comorbidities. Cana was administered at doses of either 100 or 300 mg per day based on the estimated glomerular filtration rate (eGFR) value of DN individuals, with a mean follow‐up of 6 months. Additionally, THP‐1 monocytes were exposed to HGM (33.3 mM glucose with a cytokine cocktail of TNF‐α and IFN‐γ at 50 ng/mL each) to evaluate the relative levels of ERS, OS markers, and nuclear factor erythroid 2‐related factor 2 (Nrf2), the transcription factor regulating cellular redox, which is downregulated in diabetes. Our results revealed that ERS markers GRP78 and PERK, as well as OS markers TXNIP and p22phox, were elevated in both DN patients and HGM‐treated THP‐1 monocytes and were reduced by Cana intervention. Furthermore, Cana regulated the phosphorylation of Nrf2, Akt, and EIF2α in HGM‐treated monocytes. In conclusion, our findings highlight the role of Cana in activating Nrf2, thereby attenuating ERS and OS to mitigate DN progression. [ABSTRACT FROM AUTHOR]

Objective: Signal regulatory protein α (SIRPα) is found primarily on myeloid cells, including macrophages and neutrophils; binds to CD47; and regulates phagocytosis, antigen presentation, cellular fusion, cell proliferation, and migration. Therefore, SIRPα may be involved in the pathogenesis of autoimmune diseases, including systemic vasculitis. This study aimed to assess SIRPα expression in tissue samples from patients with vasculitis. Methods: Immunohistochemical staining for SIRPα was performed on temporal artery (TA), kidney, and lung biopsy samples from patients with giant cell arteritis (GCA), patients with microscopic polyangiitis (MPA), patients with granulomatosis with polyangiitis (GPA), and patients without vasculitis. A score of SIRPα+ expression was calculated, derived from the percentages of monocytes, macrophages, and dendritic cells and neutrophils with different staining intensities in affected tissues. Results: A total of 46 samples from patients with different vasculitides (GCA, MPA, and GPA) were included in the study. Tissue samples included TA samples from 15 patients with GCA; kidney samples from 11 and 9 patients with GPA and MPA, respectively; and lung samples from 11 patients with GPA. Most tissue samples from patients with active vasculitis (15 of 15 TA samples, 17 of 20 kidney samples, and 9 of 11 lung samples) showed SIRPα staining. SIRPα staining intensity was less in kidney samples compared to TA and lung samples. Conclusion: This study demonstrates high‐level expression of SIRPα in macrophages and monocytes in affected tissue in systemic vasculitis. These findings provide a foundation for further studies exploring the role of the SIRPα–CD47 pathway in the pathogenesis of systemic vasculitis and the potential for the blockade of SIRPα and/or the depletion of SIRPα+ cells as treatment of systemic vasculitis. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus is a medically important pathogen. Previously, using murine CMV (MCMV), we provided evidence that both neutralizing and nonneutralizing antibodies can confer protection from viral infection in vivo. In this study, we report that serum derived from infected animals had a greater protective capacity in MCMV‐infected RAG−/− mice than serum from animals immunized with purified virus. The protective activity of immune serum was strictly dependent on functional Fcγ receptors (FcγR). Deletion of individual FcγRs or combined deletion of FcγRI and FcγRIV had little impact on the protection afforded by serum. Adoptive transfer of CD115‐positive cells from noninfected donors demonstrated that monocytes represent important cellular mediators of the protective activity provided by immune serum. Our studies suggest that Fc–FcγR interactions and monocytic cells are critical for antibody‐mediated protection against MCMV infection in vivo. These findings may provide new avenues for the development of novel strategies for more effective CMV vaccines or antiviral immunotherapies. [ABSTRACT FROM AUTHOR]

Aim: Evidence suggests that translocation of oral pathogens through the oral–gut axis may induce intestinal dysbiosis. This study aimed to evaluate the impact of a highly leukotoxic Aggregatibacter actinomycetemcomitans (Aa) strain on the gut microbiota, intestinal mucosal integrity and immune system in healthy mice. Methods: Eight‐week‐old male C57BL6 mice were divided into control (n = 16) and JP2 groups (n = 19), which received intragastric gavage with PBS and with a suspension of Aa JP2 (HK921), respectively, twice a week for 4 weeks. Colonic lamina propria, fecal material, serum, gingival tissues, and mandibles were obtained for analyses of leukocyte populations, inflammatory mediators, mucosal integrity, alveolar bone loss, and gut microbiota. Differences between groups for these parameters were examined by non‐parametric tests. Results: The gut microbial richness and the number of colonic macrophages, neutrophils, and monocytes were significantly lower in Aa JP2‐infected mice than in controls (p <.05). In contrast, infected animals showed higher abundance of Clostridiaceae, Lactobacillus taiwanensis, Helicobacter rodentium, higher levels of IL‐6 expression in colonic tissues, and higher splenic MPO activity than controls (p <.05). No differences in tight junction expression, serum endotoxin levels, and colonic inflammatory cytokines were observed between groups. Infected animals presented also slightly more alveolar bone loss and gingival IL‐6 levels than controls (p <.05). Conclusion: Based on this model, intragastric administration of Aa JP2 is associated with changes in the gut ecosystem of healthy hosts, characterized by less live/recruited myeloid cells, enrichment of the gut microbiota with pathobionts and decrease in commensals. Negligible levels of colonic pro‐inflammatory cytokines, and no signs of mucosal barrier disruption were related to these changes. [ABSTRACT FROM AUTHOR]

Recent studies have highlighted the importance of microglia as key immunomodulators in a variety of neuropsychiatric diseases. Postmortem brain analysis and positron emission tomography are representative research approaches to assess microglial activation in human patients and this research has revealed microglial activation in the brains of patients with various neuropsychiatric disorders. However, only limited aspects of microglial activation can be assessed with these methods. To overcome the technical and ethical limitations of collecting human‐derived microglia in brain biopsies, we first developed a method to generate directly induced microglia‐like (iMG) cells from fresh human peripheral blood monocytes in 2014. These iMG cells can be used to perform dynamic morphological and molecular analyses regarding phagocytic capacity and cytokine release following stress stimulation at the cellular level. Patient‐derived iMG cells can potentially serve as an important surrogate marker for estimating microglial activation in the human brain, and may provide previously unknown insights into the dynamic pathophysiology of microglia in patients with neuropsychiatric disorders. Thus, the iMG‐based technology could be used as a valuable reverse translational tool and provide new insights into the dynamic molecular pathophysiology of microglia in a wide variety of psychiatric and physical disorders. [ABSTRACT FROM AUTHOR]

Cellular metabolism is a key determinant of immune cell function. Here we found that CD14+ monocytes from Sub‐Saharan Africans produce higher levels of IL‐10 following TLR‐4 stimulation and are bioenergetically distinct from monocytes from Europeans. Through metabolomic profiling, we identified the higher IL‐10 production to be driven by increased baseline production of NADPH oxidase‐dependent reactive oxygen species, supported by enhanced pentose phosphate pathway activity. Together, these data indicate that NADPH oxidase‐derived ROS is a metabolic checkpoint in monocytes that governs their inflammatory profile and uncovers a metabolic basis for immunological differences across geographically distinct populations. [ABSTRACT FROM AUTHOR]

Migraine (MI) is the most common neurological disease, affecting with 20% of the world population. A subset of 25% of MI patients showcase concurrent vestibular symptoms, which may classify as vestibular migraine (VM). Meniere's disease (MD) is a complex inner ear disorder defined by episodes of vertigo associated with tinnitus and sensorineural hearing loss with a significant autoimmune/autoinflammatory contribution, which symptoms overlap with VM. Blood samples from 18 patients with MI (5), VM (5) and MD (8) and 6 controls were collected and compared in a case–control study. Droplet‐isolated nuclei from mononuclear cells used to generate scRNAseq and scATACseq data sets from MI, VM and MD. MI and VM have no differences in their immune transcriptome; therefore, they were considered as a single cluster for further analyses. Natural Killer (NK) cells transcriptomic data support a polarisation triggered by Type 1 innate immune cells via the release of interleukin (IL)‐12, IL‐15 and IL‐18. According to the monocyte scRNAseq data, there were two MD clusters, one inactive and one driven by monocytes. The unique pathways of the MI + VM cluster were cellular responses to metal ions, whereas MD monocyte‐driven cluster pathways showed responses to biotic stimuli. MI and MD have different immune responses. These findings support that MI and VM have a Type 1 immune lymphoid cell response, and that there are two clusters of MD patients, one inactive and one Monocyte‐driven. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusion Aging skin, exacerbated by external factors like UV radiation and pollutants, is a major cosmetic concern. Taurine, renowned for its antioxidant and anti‐inflammatory properties, may combat skin aging. We performed mendelian randomization (MR) analysis to investigate the causal link between taurine and immune cells linked to skin aging.To investigate the association between taurine and immune cells using mendelian randomization, to thereby explore the mechanism through which taurine exerts anti‐aging effects on the skin via immune modulation.A MR approach was employed using taurine‐level data from the Ieu Open GWAS Project and immunocyte traits from a large European cohort. MR‐Egger regression, weighted median estimation, and inverse variance weighting all provided statistical insights into causality. Sensitivity analyses assessed the heterogeneity and pleiotropy among the genetic instruments used.MR analysis identified a causal relationship between taurine levels and 10 immunocyte phenotypes, with taurine found to be negatively and positively associated with three and seven phenotypes, respectively. Sensitivity analysis revealed no significant heterogeneity or pleiotropy, suggesting reliable MR findings.This study provides insights into the immunological pathways by which taurine contributes to skin anti‐aging effects, suggesting that increasing taurine levels could offer a novel strategy for anti‐aging skincare. [ABSTRACT FROM AUTHOR]

Objectives: Increasing evidence suggests that Fc‐mediated antibody effector functions have an important role in protection against respiratory viruses, including SARS‐CoV‐2. However, limited data are available on the potential differences in the development, heterogeneity and durability of these responses in children compared to adults. Methods: Here, we assessed the development of spike S1‐specific serum antibody‐dependent cellular phagocytosis (ADCP), complement deposition (ADCD) and natural killer cell activation (ADNKA), alongside specific antibody binding concentrations (IgG, IgA and IgM) and IgG avidity in healthy adults (n = 38, 18–56 years) and children (n = 21, 5–16 years) following primary SARS‐CoV‐2 infection, with a 10‐month longitudinal follow‐up. Differences between groups were assessed using a nonparametric Kruskal–Wallis test with Dunn's multiple comparisons test. Results: We found similar (functional) antibody responses in children compared to adults, with a tendency for increased durability in children, which was statistically significant for ADCD (P < 0.05). While ADNKA was strongly reduced in both adults (P < 0.001) and children (P < 0.05) at the latest time point, ADCP remained relatively stable over time, possibly relating to an increase in avidity of the spike‐specific antibodies (P < 0.001). Finally, the ADNKA capacity relative to antibody concentration appeared to decrease over time in both children and adults. Conclusion: In conclusion, our data provide novel insights into the development of SARS‐CoV‐2‐specific antibody Fc‐mediated effector functions in children and adults. An increased understanding of these characteristics in specific age populations is valuable for the future design of novel and improved vaccination strategies for respiratory viruses such as SARS‐CoV‐2. [ABSTRACT FROM AUTHOR]

Problem: Preeclampsia (PE) and fetal growth restriction (FGR) are often associated with maternal inflammation and an increased risk of cardiovascular and metabolic disease in the affected mothers. The mechanism responsible for this increased risk of subsequent disease may involve reprogramming of innate immune cells, characterized by epigenetic modifications. Method of Study: Circulating monocytes from women with PE, FGR, or uncomplicated pregnancies (control) were isolated before labor. Cytokine release from monocytes following exposure to lipopolysaccharide (LPS) and the presence of lysine 4‐trimethylated histone 3 (H3K4me3) within TNF promoter sequences were evaluated. Single‐cell transcriptomic profiles of circulating monocytes from women with PE or uncomplicated pregnancies were assessed. Results: Monocytes from women with PE or FGR exhibited increased IL‐10 secretion and decreased IL‐1β and GM‐CSF secretion in response to LPS. While TNFα secretion was not significantly different in cultures of control monocytes versus those from complicated pregnancies with or without LPS exposure, monocytes from complicated pregnancies had significantly decreased levels of H3K4me3 associated with TNF promoter sequences. Cluster quantification and pathway analysis of differentially expressed genes revealed an increased proportion of anti‐inflammatory myeloid cells and a lower proportion of inflammatory non‐classical monocytes among the circulating monocyte population in women with PE. Conclusions: Monocytes from women with PE and FGR exhibit an immune tolerance phenotype before initiation of labor. Further investigation is required to determine whether this tolerogenic phenotype persists after the affected pregnancy and contributes to increased risk of subsequent disease. [ABSTRACT FROM AUTHOR]

Aging is a multifaceted process impacting cells, tissues, organs, and organ systems of the body. Like other systems, aging affects both the adaptive and the innate components of the immune system, a phenomenon known as immunosenescence. The deregulation of the immune system puts elderly individuals at higher risk of infection, lower response to vaccines, and increased incidence of cancer. In the Western world, overnutrition has increased the incidence of obesity (linked with chronic inflammation) which increases the risk of metabolic syndrome, cardiovascular disease, and cancer. Aging is also associated with inflammaging a sterile chronic inflammation that predisposes individuals to age‐associated disease. Genetic manipulation of the nutrient‐sensing pathway, fasting, and calorie restriction (CR) has been shown to increase the lifespan of model organisms. As well in humans, fasting and CR have also been shown to improve different health parameters. Yet the direct effect of fasting and CR on the aging immune system needs to be further explored. Identifying the effect of fasting and CR on the immune system and how it modulates different parameters of immunosenescence could be important in designing pharmacological or nutritional interventions that slow or revert immunosenescence and strengthen the immune system of elderly individuals. Furthermore, clinical intervention can also be planned, by incorporating fasting or CR with medication, chemotherapy, and vaccination regimes. This review discusses age‐associated changes in the immune system and how these changes are modified by fasting and CR which add information on interventions that promote healthy aging and longevity in the growing aging population. [ABSTRACT FROM AUTHOR]

The monocyte–macrophage system plays an important role in phagocytosis of pathogens and cellular debris following infection or tissue injury in several pathophysiological conditions. We examined ENaC/ASIC subunit transcript expression and the importance of select subunits in migration of bone marrow derived monocytes (freshly isolated) and macrophages (monocytes differentiated in culture). We also examined the effect of select subunit deletion on macrophage phenotype. BM monocytes were harvested from the femurs of male and female WT and KO mice (6–12 weeks of age). Our results show that α, β, γENaC, and ASIC1‐5 transcripts are expressed in BM macrophages and monocytes to varying degrees. At least αENaC, βENaC, and ASIC2 subunits contribute to chemotactic migration responses in BM monocyte–macrophages. Polarization markers (CD86, soluble TNFα) in BM macrophages from mice lacking ASIC2a plus βENaC were shifted towards the M1 phenotype. Furthermore, select M1 phenotypic markers were recovered with rescue of βENaC or ASIC2. Taken together, these data suggest that βENaC and ASIC2 play an important role in BM macrophage migration and loss of βENaC and/or ASIC2 partially polarizes macrophages to the M1 phenotype. Thus, targeting ENaC/ASIC expression in BM macrophages may regulate their ability to migrate to sites of injury. [ABSTRACT FROM AUTHOR]

Sepsis is one of the major challenges in intensive care units, characterized by the complexity of the host immune status. To gain a deeper understanding of the pathogenesis of sepsis, it is crucial to study the phenotypic changes in immune cells and their underlying molecular mechanisms. We conducted Summary data‐based Mendelian randomization analysis by integrating genome‐wide association studies data for sepsis with expression quantitative trait locus data, revealing a significant decrease in the expression levels of 17 biomarkers in sepsis patients. Furthermore, based on single‐cell RNA sequencing data, we elucidated potential molecular mechanisms at single‐cell resolution and identified that LGALS9 inhibition in sepsis patients leads to the activation and differentiation of monocyte and T‐cell subtypes. These findings are expected to assist researchers in gaining a more in‐depth understanding of the immune dysregulation in sepsis. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) monocyte and macrophage therapies are promising solid tumor immunotherapies that can overcome the challenges facing conventional CAR T cell therapy. mRNA lipid nanoparticles (mRNA‐LNPs) offer a viable platform for in situ engineering of CAR monocytes with transient and tunable CAR expression to reduce off‐tumor toxicity and streamline cell manufacturing. However, identifying LNPs with monocyte tropism and intracellular delivery potency is difficult using traditional screening techniques. Here, ionizable lipid design and high‐throughput in vivo screening are utilized to identify a new class of oxidized LNPs with innate tropism and mRNA delivery to monocytes. A library of oxidized (oLNPs) and unoxidized LNPs (uLNPs) is synthesized to evaluate mRNA delivery to immune cells. oLNPs demonstrate notable differences in morphology, ionization energy, and pKa, thereby enhancing delivery to human macrophages, but not T cells. Subsequently, in vivo library screening with DNA barcodes identifies an oLNP formulation, C14‐O2, with innate tropism to monocytes. In a proof‐of‐concept study, the C14‐O2 LNP is used to engineer functional CD19‐CAR monocytes in situ for robust B cell aplasia (45%) in healthy mice. This work highlights the utility of oxidized LNPs as a promising platform for engineering CAR macrophages/monocytes for solid tumor CAR monocyte therapy. [ABSTRACT FROM AUTHOR]

In 2023, there was a significant increase in the number of articles published on microglia, the primary immune cells of the brain. These articles explored the role of microglia in brain development, health, and disease. One study identified the role of the Rho GTPase Rac1 in microglia biology and brain plasticity, while another study focused on the cell-autonomous effects of APOE4 expression in microglia in Alzheimer's disease. Additionally, a new protocol called FEAST was introduced to study microglia phagocytosis. These advancements have the potential to greatly impact biomedical research and our understanding of microglia biology. [Extracted from the article]

Antiphospholipid syndrome (APS) is characterized by thrombus formation, poor pregnancy outcomes, and a proinflammatory response. H3K4me3‐related monocytes activation are key regulators of APS pathogenesis. Therefore, H3K4me3 CUT&Tag and ATAC‐seq are performed to examine the epigenetic profiles. The results indicate that the H3K4me3 signal and chromatin accessibility at the FOXJ2 promoter are enhanced in an in vitro monocyte model by stimulation with β2GPI/anti‐β2GPI, which mimics APS, and decreases after OICR‐9429 administration. Furthermore, FOXJ2 is highly expressed in patients with primary APS (PAPS) and is the highest in patients with triple‐positive antiphospholipid antibodies (aPLs). Mechanistically, FOXJ2 directly binds to the SLAMF8 promoter and activates SLAMF8 transcription. SLAMF8 further interacts with TREM1 to stimulate TLR4/NF‐κB signaling and prohibit autophagy. Knockdown of FOXJ2, SLAMF8, or TREM1 blocks TLR4/NF‐κB and provokes autophagy, subsequently inhibiting the release of inflammatory and thrombotic indicators. A mouse model of vascular APS is established via β2GPI intraperitoneal injection, and the results suggest that OICR‐9429 administration attenuates the inflammatory response and thrombus formation by inactivating FOXJ2/SLAMF8/TREM1 signaling. These findings highlight the overexpression of H3K4me3‐mediated FOXJ2 in APS, which consequently accelerates APS pathogenesis by triggering inflammation and thrombosis via boosting the SLAMF8/TREM1 axis. Therefore, OICR‐9429 is a promising candidate drug for APS therapy. [ABSTRACT FROM AUTHOR]

Aim: To investigate the effect of cholecalciferol supplementation on hand grip strength, walking speed, and expression of vitamin D receptor (VDR), interleukine‐6 (IL‐6) and insulin‐like growth factor‐1 (IGF‐1) in monocyte in pre‐frail older adults. Methods: We conducted a randomized double‐blinded placebo‐controlled clinical trial for 12 weeks, involving 120 pre‐frail older adults who were randomized to the cholecalciferol group (cholecalciferol 4000 IU/day) or the placebo group. All subjects were given calcium lactate 500 mg/day. Hand grip strength and walking speed, as primary outcomes, were analyzed using intention‐to‐treat analysis. The expression of VDR, IGF‐1 and IL‐6 in monocytes, as secondary outcomes, were analyzed using per‐protocol analysis. Results: After a 12‐week intervention, there was a significant increase in serum 25(OH)D levels in both groups, with the increase being higher in the cholecalciferol group than in the placebo group (49.05 vs. 24.01 ng/mL; P < 0.001). No statistically significant differences were observed in hand grip strength (P = 0.228) and walking speed (P = 0.734) between the groups. There were no differences in the expression of VDR (P = 0.513), IL‐6 (P = 0.509), and IGF‐1 (P = 0.503) monocytes between the groups. Conclusions: Cholecalciferol supplementation for 12 weeks increased serum 25(OH)D levels among pre‐frail older adults. However, it did not improve hand grip strength and walking speed, and nor did it change the expression of VDR, IL‐6, and IGF‐1 in monocytes. Geriatr Gerontol Int 2024; 24: 554–562. [ABSTRACT FROM AUTHOR]

Introduction: Cell population data (CPD) parameters may be putative biomarkers for the screening of various diseases including some infections and myelodysplastic syndrome. This study aimed to establish the age‐ and sex‐specific reference intervals (RIs) for the CPD parameters in the Korean population. Methods: The reference population for the RIs of CPD parameters comprised 124 856 subjects aged 20–99 years. CPD parameters were obtained from Sysmex XN‐2000 (Kobe, Japan) datasets from 17 health promotion centers in 13 South Korean cities. We determined significant partitions for age and sex, and calculated RIs according to Clinical and Laboratory Standards Institute C28‐A3 guidelines. Results: The side scattered light intensity in the neutrophil area and the lymphocyte area did not require sex‐related partitioning except in those over the age of 50, among whom the lower limit (LL) and upper limit (UL) were lower in females. However, the side scattered light distribution width in the lymphocyte area required age‐ and sex‐related partitioning, in which LL and UL were higher in females. The LL and UL of the fluorescent light distribution width were higher in males in the neutrophil area and higher in females in the lymphocyte area, but age‐related partitioning was not required. The forward scattered light intensity in the neutrophil area, lymphocyte area, and monocyte area did not require age‐related partitioning in males. Conclusion: This study has determined comprehensive age‐ and sex‐specific RIs for CPD parameters, which could help to prove the clinical significance of these parameters in the Sysmex XN‐2000. [ABSTRACT FROM AUTHOR]

Background: Numerous studies have demonstrated that Absent in Melanoma 2 (AIM2) is upregulated in aortic plaques, especially in Vascular Smooth Muscle Cells in Coronary Artery Disease (CAD), and is related to inflammasome‐induced inflammation. However, the underlying mechanism of this phenomenon and the role of AIM2 in atherosclerosis remained unclear. Methods: This study enrolled 133 CAD patients and 123 controls. We isolated Peripheral Blood Leukocytes (PBLs) and the mRNA expression of AIM2 inflammasome and its downstream genes (ASC, Caspase‐1, IL‐1β, and IL‐18) were detected by real‐time quantitative PCR (qPCR). We assessed correlations between AIM2 expressions and clinical characteristics by multiple linear regression and spearman's correlation. The THP‐1 cells cultured in poly(dA:dT), A151, interferon‐gamma (IFN‐γ), AG490, or JC2‐11. And then the mRNA and protein levels of AIM2, ASC, Caspase‐1, IL‐1β, IL‐18, GSDMD, and STAT1 were analyzed by qPCR and Western blot analysis, respectively. The migration and adhesive capacity of THP‐1 cells was assessed using an inverted microscope and an inverted fluorescence microscope, respectively. Results: In this study, we found that expressions of components of AIM2 inflammasome and its downstream genes (ASC, Caspase‐1, IL‐1β, and IL‐18), were all increased in PBLs of CAD patients, which indicated the inflammasome activation. AIM2 inflammasome activation further induced pyroptosis, and stimulated migration and adhesion in monocyte cell lines, which was regulated by IFN‐γ probably through JAK2/STAT1 pathway. In addition, AIM2 expressions were positively correlated with systemic inflammatory indicators as an independent risk factor for CAD. Conclusions: In conclusion, increased AIM2 expression, induced by the IFN‐γ/JAK2/STAT1 signal, orientates monocytes to inflammatory status or even pyroptosis through AIM2 inflammasome activation, which is involved in the development of CAD. [ABSTRACT FROM AUTHOR]

Myocarditis has emerged as a rare but lethal immune checkpoint inhibitor (ICI)‐associated toxicity. However, the exact mechanism and the specific therapeutic targets remain underexplored. In this study, we aim to characterise the transcriptomic profiles based on single‐cell RNA sequencing from ICI‐related myocarditis. Peripheral blood mononuclear cell (PBMC) samples were collected from four groups for single‐cell RNA sequencing: (1) patients with newly diagnosed lung squamous cell carcinoma before treatment (Control Group); (2) patients with lung squamous cell carcinoma with PD‐1 inhibitor therapy who did not develop myocarditis (PD‐1 Group); (3) patients during fulminant ICI‐related myocarditis onset (Myocarditis Group); and (4) Patients with fulminant ICI‐related myocarditis during disease remission (Recovery Group). Subcluster determination, functional analysis, single‐cell trajectory and cell–cell interaction analysis were performed after scRNA‐seq. Bulk‐RNA sequencing was performed for further validation. Our results revealed the diversity of cellular populations in ICI‐related myocarditis, marked by their distinct transcriptional profiles and biological functions. Monocytes, NKs as well as B cells contribute to the regulation of innate immunity and inflammation in ICI‐related myocarditis. With integrated analysis of scRNA‐seq and bulk sequencing, we identified S100A protein family as a potential serum marker for ICI‐related myocarditis. Our study has created a cell atlas of PBMC during ICI‐related myocarditis, which would shed light on the pathophysiological mechanism and potential therapeutic targets of ICI‐related myocarditis in continuous exploration. [ABSTRACT FROM AUTHOR]

Background: Lipofuscin-like cytoplasmic inclusions have been reported in human blood neutrophils and monocytes but have not been described in dogs. In people, these “green granules of death” have been associated with moderate to severe hepatocellular injury and high mortality. Objectives: To describe clinicopathologic abnormalities, diagnoses, and outcomes of dogs with greenish inclusions in blood neutrophils or monocytes, and to determine if the inclusions have features of lipofuscin. Methods: Clinical cases were identified prospectively through routine evaluation of CBC samples. Leukocyte inclusions were characterized with routine staining and assessed for iron and autofluorescence. Additional cases were identified by examination of archived blood smears from dogs meeting search criteria for hepatocellular injury, and clinicopathologic findings were recorded. Results: All 7 prospectively identified dogs with inclusions had inflammation and moderate to marked increases in serum alanine aminotransferase (ALT) activity, as did the 4 dogs identified from the 97 meeting retrospective search criteria. The inclusions were Prussian blue–negative (5/5) with broad-spectrum autofluorescence (5/5) and the appearance of lipofuscin with and without Wright staining. Most clinical diagnoses involved hepatic disorders (5/7 prospective and 3/4 retrospective cases) or pancreatitis (3/7 prospective and 2/4 retrospective cases), and some involved both; 8 of 11 dogs died within 7 days of admission. Conclusions: Blue-green cytoplasmic inclusions uncommonly found in blood neutrophils ± monocytes of routine canine blood smears have stained and unstained properties of lipofuscin and suggest the presence of hepatocellular injury, often severe. Reporting these inclusions is recommended to guide clinical management. [ABSTRACT FROM AUTHOR]

The article comments on a study which investigated the role of exercise on tumour necrosis factor-alpha production and monocyte polarization. Topics discussed include the exercises performed by the study participants, such as moderate continuous exercise, heavy continuous exercise and heavy interval exercise, alterations in circulating immune cells and cytokines elicited by the exercises, and the implications and opportunities for application of findings.

Summary: Training and priming of innate immune cells involve preconditioning by PAMPs, DAMPs, and/or cytokines that elicits stronger induction of inflammatory genes upon secondary challenge. Previous models distinguish training and priming based upon whether immune activation returns to baseline prior to secondary challenge. Tolerance is a protective mechanism whereby potent stimuli induce refractoriness to secondary challenge. Training and priming are important for innate memory responses that protect against infection, efficacy of vaccines, and maintaining innate immune cells in a state of readiness; tolerance prevents toxicity from excessive immune activation. Dysregulation of these processes can contribute to pathogenesis of autoimmune/inflammatory conditions, post‐COVID‐19 hyperinflammatory states, or sepsis‐associated immunoparalysis. Training, priming, and tolerance regulate similar "signature" inflammatory genes such as TNF, IL6, and IL1B and utilize overlapping epigenetic mechanisms. We review how interferons (IFNs), best known for activating JAK–STAT signaling and interferon‐stimulated genes, also play a key role in regulating training, priming, and tolerance via chromatin‐mediated mechanisms. We present new data on how monocyte‐to‐macrophage differentiation modulates IFN‐γ‐mediated priming, affects regulation of AP‐1 and CEBP activity, and attenuates superinduction of inflammatory genes. We present a "training‐priming continuum" model that integrates IFN‐mediated priming into current concepts about training and tolerance and proposes a central role for STAT1 and IRF1. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to establish a nomogram for predicting the probability of testicular salvage after testicular torsion in children. Methods: We retrospectively collected data of children with testicular torsion who were treated at Shenzhen Children's Hospital between September 2005 and August 2022. Of the training cohort, 113 patients who underwent orchiectomy and five with testicular atrophy after orchiopexy were included in the failed testicular salvage group. Additionally, 37 patients who underwent orchiopexy without postoperative testicular atrophy were included in the successful testicular salvage group. The predictive factors affecting testicular salvage were determined using univariate and multivariate logistic regression analyses; a nomogram was constructed. The nomogram was verified using data from the validation group. Results: Using multivariate logistic regression analysis, the independent risk factors of testicular salvage after testicular torsion were symptom duration (p = 0.034), intratesticular blood flow (p = 0.003), spermatic cord torsion degree (p = 0.037), and monocyte count (odds ratio: 0.012, p = 0.036). A nomogram was established based on these four risk factors. In the training cohort, the area under the receiver operating characteristic curve was 0.969. The area under the receiver operating characteristic curve of the verification cohort was 0.965, indicating good discrimination ability of the nomogram. Increased symptom duration without intratesticular blood flow increased the monocyte count and spermatic cord torsion degree and decreased the success rate of testicular salvage. Conclusion: This prediction model could obtain the corresponding probability of testicular salvage according to the clinical characteristics of different patients with testicular torsion, providing reference for clinicians and parents. [ABSTRACT FROM AUTHOR]

Resident macrophages of various mammalian organs are characterized by several distinctive features in their gene expression profile and phenotype, including involvement in the regulation of organ functions, as well as reduced sensitivity to proinflammatory activation factors. The reasons for the formation of such a specific phenotype remain the subject of intensive research. Some papers emphasize the role of the origin of organ macrophages. Other studies indicate that monocytes that develop in the red bone marrow are also able to form resident macrophages with a phenotype characteristic of a particular organ, but this requires appropriate microenvironmental conditions. In this article, we studied the possibility of differentiation of monocyte‐derived macrophages into cells with a Kupffer‐like phenotype under the influence of the main stromal components of Kupffer cells macrophage niche: Ito cells, liver sinusoid endotheliocytes and hepatocyte growth factor (HGF). It was found that Kupffer cells are characterized by several features, including increased expression of transcription factors Spic and Id3, as well as MUP family genes, Clusterin and Ngp genes. In addition, Kupffer cells were characterized by a higher proliferative activity. The expression of marker genes of Kupffer cells (i.e. Id3, Spic, Marco and Timd4) increased in monocyte‐derived macrophages during coculture with Ito cells, liver sinusoid endothelial cells, macrophage colony–stimulating factor and HGF cells only by 3 days. However, the expression level of these genes was always higher in Kupffer cells. In addition, a complete coincidence of the expressed gene profile in monocyte‐derived macrophages and Kupffer cells did not occur even after 3 days of culturing. [ABSTRACT FROM AUTHOR]

Apolipoprotein E (ApoE) has been associated with several diseases including Parkinson's disease, Alzheimer's and multiple sclerosis. ApoE also has documented immunomodulatory functions. We investigated gene expression in circulating monocytes and in bone marrows of patients with visceral leishmaniasis (VL) living in an endemic area in Bihar, India, and contrasted these with control healthy subjects or other diagnostic bone marrows from individuals in the same region. Samples from VL patients were obtained prior to initiating treatment. Our study revealed significant upregulated expression of the apoE transcript in patients with VL. Furthermore, the levels of ApoE protein were elevated in serum samples of subjects with VL compared with healthy endemic controls. These observations may provide clues regarding the complex interactions between lipid metabolism and immunoregulation of infectious and inflammatory diseases. [ABSTRACT FROM AUTHOR]

The different immune system cells communicate and coordinate a response using a complex and evolved language of cytokines and chemokines. These cellular interactions carry out multiple functions in distinct cell types with numerous developmental outcomes. Despite the plethora of different cytokines and their cognate receptors, there is a restricted number of signal transducers and activators to control immune responses. Herein, we report on a new class of immunomodulatory signaling molecules based on volatile molecules (VMs, namely, volatile organic compounds [VOCs]), by which they can affect and/or control immune cell behavior and transcriptomic profile without any physical contact with other cells. The study demonstrates the role of VMs by analyzing non‐contact cell communication between normal and cancerous lung cells and U937 monocytes, which are key players in the tumor microenvironment. Integrated transcriptome and proteome analyses showed the suggested regulatory role of VMs released from normal and cancer cells on neighboring monocytes in several molecular pathways, including PI3K/AKT, PPAR, and HIF‐1. Presented data provide an initial platform for a new class of immunomodulatory molecules that can potentially mirror the genomic and proteomic profile of cells, thereby paving the way toward non‐invasive immunomonitoring. [ABSTRACT FROM AUTHOR]

Red‐eared sliders (Trachemys scripta elegans), as one of the 100 most threatening aliens, have stronger immunity than the native species in response to environmental stress. Blood cells are an important component of immunity in the body. However, the blood cell researches of turtle are still in the traditional blood cell classification and morphological structure observation. Furthermore, turtle granulocytes cannot be accurately identified using traditional methods. Single‐cell RNA sequencing techniques have been successfully implemented to study cells based on the mRNA expression patterns of each cell. The present study profiled the transcriptomes of peripheral blood cells in red‐eared sliders to construct a single‐cell transcriptional landscape of the different cell types and explored environmental adaptation mechanism from the perspective of hematology. All 14 transcriptionally distinct clusters (platelets, erythrocytes1, erythrocytes2, CSF1R monocytes, POF1B monocytes, neutrophils, GATA2high basophils, GATA2low basophils, CD4 T cells, CD7 T cells, B cells, ACKR4 cells, serotriflin cells, and ficolin cells) were identified in the peripheral blood cells of the red‐eared sliders. In particular, a subtype of erythrocytes (erythrocytes1) that expressed immune signals was identified. Peripheral blood cells were grouped into three lineages: platelet, erythroid/lymphoid, and myeloid cell lineages. Furthermore, based on differentiation trajectory and up‐regulated gene expression, ACKR4 cells were newly identified as lymphocytes, and serotriflin and ficolin cells as granulocytes. The single‐cell transcriptional atlas of the peripheral blood cells in red‐eared sliders provided in the present study will offer a comprehensive transcriptome reference for the exploration of physiological and pathological hematology in this species. [ABSTRACT FROM AUTHOR]

Background: The exact cause of intracranial aneurysms (IA) is still unclear. However, pro‐inflammatory factors are known to contribute to IA progression. The specific changes in the immune microenvironment of IAs remain largely unexplored. Methods: This study analyzed single‐cell sequencing data from a male mouse model of brain aneurysm, focusing on samples before and after elastase‐induced Willis aneurysms. The data helped identify eight distinct cell subpopulations: fibroblasts, macrophages, NK cells, endothelial cells, B cells, granulocytes, and monocytes. The study also involved bulk RNA sequencing of 97 IA samples, utilizing ssGSEA and CIBERSORT algorithms for analysis. Intercellular communication among these cells was inferred to understand the immune dynamics in IA. Results: The study found that fibroblasts and macrophages are predominant in various disease states of IA. Notably, the onset of IA was marked by a significant increase in fibroblasts and a decrease in macrophages. There was a marked increase in cellular interactions, especially involving macrophages, at the onset of the disease. Through enrichment analysis, 12 potential immunogenic biomarkers were identified. Of these, Rgs1 emerged as a critical molecule in IA formation, confirmed through secondary validation in a single‐cell sequencing dataset. Conclusion: This comprehensive analysis of immune cell composition and intercellular communication in IA tissues highlights the significant roles of macrophages and the molecule Rgs1. These findings shed light on the physiological and pathological conditions of IA, offering new insights into its immune microenvironment. [ABSTRACT FROM AUTHOR]

Acetaminophen overdose is a leading cause of acute liver failure (ALF). Despite the pivotal role of the inflammatory microenvironment in the progression of advanced acetaminophen‐induced liver injury (AILI), a comprehensive understanding of the underlying cellular interactions and molecular mechanisms remains elusive. Mas is a G protein‐coupled receptor highly expressed by myeloid cells; however, its role in the AILI microenvironment remains to be elucidated. A multidimensional approach, including single‐cell RNA sequencing, spatial transcriptomics, and hour‐long intravital imaging, is employed to characterize the microenvironment in Mas1 deficient mice at the systemic and cell‐specific levels. The characteristic landscape of mouse AILI models involves reciprocal cellular communication among MYC+CD63+ endothelial cells, MMP12+ macrophages, and monocytes, which is maintained by enhanced glycolysis and the NF‐κB/TNF‐α signaling pathway due to myeloid‐Mas deficiency. Importantly, the pathogenic microenvironment is delineated in samples obtained from patients with ALF, demonstrating its clinical relevance. In summary, these findings greatly enhance the understanding of the microenvironment in advanced AILI and offer potential avenues for patient stratification and identification of novel therapeutic targets. [ABSTRACT FROM AUTHOR]

CD8+ T cells are critical for host antitumor responses, whereas persistent antigenic stimulation and excessive inflammatory signals lead to T cell dysfunction or exhaustion. Increasing early memory T cells can improve T cell persistence and empower T cell‐mediated tumor eradication, especially for adoptive cancer immunotherapy. Here, it is reported that tumor‐associated monocytes (TAMos) are highly correlated with the accumulation of CD8+ memory T cells in human cancers. Further analysis identifies that TAMos selectively reprogram CD8+ T cells into T central memory‐like (TCM‐like) cells with enhanced recall responses. L‐NMMA, a pan nitric oxide synthase inhibitor, can mitigate TAMo‐mediated inhibition of T cell proliferation without affecting TCM‐like cell generation. Moreover, the modified T cells by TAMo exposure and L‐NMMA treatment exhibit long‐term persistence and elicit superior antitumor effects in vivo. Mechanistically, the transmembrane protein CD300LG is involved in TAMo‐mediated TCM‐like cell polarization in a cell‐cell contact‐dependent manner. Thus, the terminally differentiated TAMo subset (CD300LGhighACElow) mainly contributes to TCM‐like cell development. Taken together, these findings establish the significance of TAMos in boosting T‐cell antitumor immunity. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic proinflammatory disease of the vascular wall resulting in narrowing of arteries due to plaque formation, thereby causing reduced blood supply that is the leading cause for diverse end‐organ damage with high mortality rates. Monocytes/macrophages, activated by elevated circulating lipoproteins, are significantly involved in the formation and development of atherosclerotic plaques. The imbalance between proinflammatory and anti‐inflammatory macrophages, arising from dysregulated macrophage polarization, appears to be a driving force in this process. Proatherosclerotic processes acting on monocytes/macrophages include accumulation of cholesterol in macrophages leading to foam cell formation, as well as dysfunctional efferocytosis, all of which contribute to the formation of unstable plaques. In recent years, microRNAs (miRs) were identified as factors that could modulate monocyte/macrophage function and may therefore interfere with the atherosclerotic process. In this review, we present effects of monocyte/macrophage‐derived miRs on atherosclerotic processes in order to reveal new treatment options using miRmimics or antagomiRs. [ABSTRACT FROM AUTHOR]

Depression is a serious public health problem, and adolescence is an 'age of risk' for the onset of Major Depressive Disorder. Recently, we and others have proposed neuroimmune network models that highlight bidirectional communication between the brain and the immune system in both mental and physical health, including depression. These models draw on research indicating that the cellular actors (particularly monocytes) and signaling molecules (particularly cytokines) that orchestrate inflammation in the periphery can directly modulate the structure and function of the brain. In the brain, inflammatory activity heightens sensitivity to threats in the cortico‐amygdala circuit, lowers sensitivity to rewards in the cortico‐striatal circuit, and alters executive control and emotion regulation in the prefrontal cortex. When dysregulated, and particularly under conditions of chronic stress, inflammation can generate feelings of dysphoria, distress, and anhedonia. This is proposed to initiate unhealthy, self‐medicating behaviors (e.g. substance use, poor diet) to manage the dysphoria, which further heighten inflammation. Over time, dysregulation in these brain circuits and the inflammatory response may compound each other to form a positive feedback loop, whereby dysregulation in one organ system exacerbates the other. We and others suggest that this neuroimmune dysregulation is a dynamic joint vulnerability for depression, particularly during adolescence. We have three goals for the present paper. First, we extend neuroimmune network models of mental and physical health to generate a developmental framework of risk for the onset of depression during adolescence. Second, we examine how a neuroimmune network perspective can help explain the high rates of comorbidity between depression and other psychiatric disorders across development, and multimorbidity between depression and stress‐related medical illnesses. Finally, we consider how identifying neuroimmune pathways to depression can facilitate a 'next generation' of behavioral and biological interventions that target neuroimmune signaling to treat, and ideally prevent, depression in youth and adolescents. [ABSTRACT FROM AUTHOR]

Introduction: The platelet‐to‐lymphocyte ratio (PLR), peripheral blood absolute monocyte count (AMC), and monocyte‐to‐lymphocyte ratio (MLR) are considered biomarkers of systemic immune and inflammation response. However, their prognostic potential in patients with myelodysplastic neoplasms (MDS) remains unclear. This study aimed to explore the predictive impact of PLR, MLR, and AMC on MDS outcomes. Methods: In total, 334 patients with primary MDS were included between January 2016 and December 2021 and were retrospectively followed up until December 31, 2022. The prognostic significance of PLR, MLR, and AMC was assessed using univariate and multivariate analyses, and predictive models were generated to estimate MDS outcomes. The area under their receiver operating curves was computed to compare the predictive power of these models. Results: Fifty‐one patients had disease progression, and 103 patients died during follow‐up. In multivariate analyses, a higher PLR was an adverse independent factor for overall survival (OS) (p = 0.011), whereas a higher AMC indicated shorter progression‐free survival (p = 0.003). The prognostic model incorporating PLR, MLR, and AMC with the Revised International Prognostic Scoring System (IPSS‐R) risk categorization showed higher performance in predicting OS than the model that only utilized the IPSS‐R category. Conclusion: Elevated PLR and increased AMC had independent prognostic value for adverse outcomes in patients with MDS. PLR, MLR, and AMC enhanced the IPSS‐R risk categorization for OS prediction in MDS. [ABSTRACT FROM AUTHOR]

Introduction: Flow cytometry‐based paroxysmal nocturnal hemoglobinuria (PNH) testing involves utilization of monoclonal antibodies against GPI‐linked proteins and FLAER. The ability of FLAER to bind to a wide variety of GPI‐linked structures and to be utilized across different leukocyte subsets is remarkable. We hypothesize that FLAER as a standalone reagent may be equally effective for detecting PNH clones. The present study intends to compare the results of a FLAER alone‐based strategy to the recommended FLAER+GPI‐linked protein‐based approach for applicability in clinical settings. Methods: EDTA‐anticoagulated blood samples from patients for PNH workup were tested for PNH by multiparametric flow cytometry. A conventional panel comprising gating markers (CD45 for WBC, CD15 for granulocytes, and CD64 for monocytes) and a combination of FLAER and GPI‐linked markers, such as CD24 and CD14, henceforth referred to as the "routine panel," was employed. Second, a "FLAER‐only panel" comprising the gating markers and FLAER alone (excluding the GPI‐linked markers CD24 and CD14) was set up. The samples were processed using the lyse‐wash‐stain‐wash technique, and events were acquired on BC Navios Ex flow cytometer (Beckman Coulter, Inc., USA) and analyzed on Kaluza Software 2.1. The presence of a PNH clone was reported at a value of ≥0.01%. Results: A total of 209 patients were tested. Both panels found a PNH clone in 20.1% of patients (n = 42/209) with a 100% concordance rate. The PNH clone range for granulocytes was 0.01%–89.68%, and for monocyte was 0.04%–96.09% in the routine panel. The range in the FLAER‐only panel for granulocytes was 0.01%–89.61%, and for monocytes, it was 0.01%–96.05%. Pearson correlation statistics revealed a significant correlation between the size of the PNH clone of granulocytes and monocytes among the two panels tested (granulocytes r = 0.9999, p < 0.0001, 95% CI = 0.9999 to 1.000; monocytes r = 0.9974, p < 0.0001, 95% CI = 0.9966–0.9980). Conclusion: Based on our results, FLAER as a standalone marker is specific and sensitive for identifying PNH clones in granulocytes and monocytes, even for high‐sensitivity PNH assay. The proposed "FLAER‐only panel" panel is efficient and cost‐effective for highly sensitive PNH testing in two different cell lineages, especially in resource‐limited clinical settings. [ABSTRACT FROM AUTHOR]

Introduction: Sepsis, a syndrome of organ dysfunction caused by an unregulated host response to infection. This study aimed to develop a novel sepsis diagnostic model of hematological parameters and evaluate its effectiveness in the early identification and prognosis of sepsis in emergency departments. Methods: A retrospective study was conducted in Emergency Department. Cell population data parameters related to monocytes and neutrophils were obtained using the Mindary BC‐6800 plus hematology analyzer. Receiver operating characteristic (ROC) curve analysis, logistic regression analysis was performed to assess the performance of the parameters and establish a diagnostic and prognostic model of sepsis, which was then verified with a validation cohort. Results: Mon_XW exhibited the best diagnostic performance (area under the ROC curve [AUC] = 0.848, 95% confidence interval [CI]: 0.810–0.885, p < 0.001), followed by Neu_Y and Neu_YW (AUC = 0.777 95% CI: 0.730–0.824, p < 0.001). Logistic regression analysis identified Mon_XW and Neu_Y as independent predictors, which were used to establish a diagnostic model named hematological parameter for sepsis (HPS). HPS demonstrated the best diagnostic performance with an AUC of 0.862 (95% CI: 0.826–0.898, p < 0.001), sensitivity of 70.0%, and specificity of 87.1%, compared to C‐reactive protein (CRP) and procalcitonin (PCT). The validation cohort also found that the positive predictive value of HPS was 70.4% and the negative predictive value was 92.2%. Conclusion: The developed HPS model showed promising diagnostic efficacy for sepsis in the emergency department, which outperformed CRP and PCT in terms of sensitivity and specificity. By enabling early identification and prognosis of sepsis, that contributes to reducing sepsis‐related mortality. [ABSTRACT FROM AUTHOR]

The 24‐h ultramarathon (UM) race is one of the most demanding competitive sports in terms of muscular and physiological exertion. In this context, predictors of UM athletes' physical performance are in high demand; however, data on the predictive capabilities of hematological variables are still sparse. In the present paper, we retrospectively took into consideration the pre‐race blood biomarker levels (including basic blood count, leukocyte subpopulations, markers of inflammation and organ function, metabolic profile, and electrolytes) of 50 UM athletes (M = 33, F = 17) who completed a 24‐h competition in order to identify a combination of analytes capable of predicting the athletic performance in terms of distance covered during the 24‐h run. The multiple regression analysis produced a model that explained a significant portion of the variance in the dependent variable, with an adjusted R‐squared value of 0.783 (F(13, 36) = 14.58, p < 0.001). A greater race distance was correlated with higher pre‐race values of hematocrit, lactate dehydrogenase (LDH), total cholesterol, HDL/LDL ratio, and triglycerides and lower levels of monocytes, eosinophils, alanine aminotransferase (ALT), gamma‐glutamyl transferase (GGT), total proteins, and sodium. This study represents the first of its kind conducted on 24‐h UM athletes that investigated the association between blood markers and endurance performance. Our model, given its promising predictive power, would serve as a starting point that will require refinement and integration with other traditional performance prediction measures, in order to support athletes and coaches in better managing the training loads during the race‐approaching phases. Highlights: A combination of pre‐race hematological parameters was found to predict the 24‐h ultramarathon race distance in ultra‐endurance athletes.A greater race distance was correlated with higher pre‐race values of hematocrit, lactate dehydrogenase, total cholesterol, HDL/LDL ratio, and triglycerides, and lower levels of monocytes, eosinophils, alanine aminotransferase, gamma‐glutamyl transferase, total proteins, and sodium.The predictive model generated by the multiple regression analysis explained a significant portion of the variance in the dependent variable (race distance), with an adjusted R‐squared value of 0.783. [ABSTRACT FROM AUTHOR]

Tumor‐associated thrombus (TAT) accounts for a high proportion of venous thromboembolism. Traditional thrombolysis and anticoagulation methods are not effective due to various complications and contraindications, which can easily lead to patients dying from TAT rather than the tumor itself. These clinical issues demonstrate the need to research diverse pathways for adjuvant thrombolysis in antitumor therapy. Previously, the phenotypic and functional transformation of monocytes/macrophages is widely reported to be involved in intratribal collagen regulation. This study finds that myeloid deficiency of the oncogene SHP2 sensitizes Ly6Clow monocyte/macrophage differentiation and can alleviate thrombus organization by increasing thrombolytic Matrix metalloproteinase (MMP) 2/9 activities. Moreover, pharmacologic inhibition by SHP099, examined in mouse lung metastatic tumor models, reduces tumor and thrombi burden in tumor metastatic lung tissues. Furthermore, SHP099 increases intrathrombus Ly6Clow monocyte/macrophage infiltration and exhibits thrombolytic function at high concentrations. To improve the thrombolytic effect of SHP099, NanoSHP099 is constructed to achieve the specific delivery of SHP099. NanoSHP099 is identified to be simultaneously enriched in tumor and thrombus foci, exerting dual tumor‐suppression and thrombolysis effects. NanoSHP099 presents a superior thrombus dissolution effect than that of the same dosage of SHP099 because of the higher Ly6Clow monocyte/macrophage proportion and MMP2/MMP9 collagenolytic activities in organized thrombi. [ABSTRACT FROM AUTHOR]

Problem: Polycystic ovary syndrome (PCOS), a prevalent endocrine-metabolic disorder, presents considerable therapeutic challenges due to its complex and elusive pathophysiology. Method of study:We employed three machine learning algorithms to identify potential biomarkers within a training dataset, comprising GSE138518, GSE155489, and GSE193123. The diagnostic accuracy of these biomarkers was rigorously evaluated using a validation dataset using area under the curve (AUC) metrics. Further validation in clinical samples was conducted using PCR and immunofluorescence techniques. Additionally, we investigate the complex interplay among immune cells in PCOS using CIBERSORT to uncover the relationships between the identified biomarkers and various immune cell types. Results: Our analysis identified ACSS2, LPIN1, and NR4A1 as key mitochondriarelated biomarkers associated with PCOS. A notable difference was observed in the immune microenvironment between PCOS patients and healthy controls. In particular, LPIN1 exhibited a positive correlation with resting mast cells, whereas NR4A1 demonstrated a negative correlation with monocytes in PCOS patients. Conclusion: ACSS2, LPIN1, and NR4A1 emerge as PCOS-related diagnostic biomarkers and potential intervention targets, opening new avenues for the diagnosis and management of PCOS. [ABSTRACT FROM AUTHOR]

Objective: We aimed to investigate the hypothesis that interferon (IFN)–stimulated gene (ISG) expression in systemic lupus erythematosus (SLE) monocytes is linked to changes in metabolic reprogramming and epigenetic regulation of ISG expression. Methods: Monocytes from healthy volunteers and patients with SLE at baseline or following IFNα treatment were analyzed by extracellular flux analysis, proteomics, metabolomics, chromatin immunoprecipitation, and gene expression. The histone demethylases KDM6A/B were inhibited using glycogen synthase kinase J4 (GSK‐J4). GSK‐J4 was tested in pristane and resiquimod (R848) models of IFN‐driven SLE. Results: SLE monocytes had enhanced rates of glycolysis and oxidative phosphorylation compared to healthy control monocytes, as well as increased levels of isocitrate dehydrogenase and its product, α‐ketoglutarate (α‐KG). Because α‐KG is a required cofactor for histone demethylases KDM6A and KDM6B, we hypothesized that IFNα may be driving "trained immune" responses through altering histone methylation. IFNα priming (day 1) resulted in a sustained increase in the expression of ISGs in primed cells (day 5) and enhanced expression on restimulation with IFNα. Importantly, decreased H3K27 trimethylation was observed at the promoters of ISGs following IFNα priming. Finally, GSK‐J4 (KDM6A/B inhibitor) resulted in decreased ISG expression in SLE patient monocytes, as well as reduced autoantibody production, ISG expression, and kidney pathology in R848‐treated BALB/c mice. Conclusion: Our study suggests long‐term IFNα exposure alters the epigenetic regulation of ISG expression in SLE monocytes via changes in immunometabolism, a mechanism reflecting trained immunity to type I IFN. Importantly, it opens the possibility that targeting histone‐modifying enzymes, such as KDM6A/B, may reduce IFN responses in SLE. [ABSTRACT FROM AUTHOR]

Aim: CCR2 (C‐C chemokine receptor type 2) plays a crucial role in inflammatory and bone metabolic diseases; however, its role in peri‐implantitis remains unclear. This study aimed to explore whether CCR2 contributes to peri‐implantitis and the treatment effects of cenicriviroc (CVC) on peri‐implant inflammation and bone resorption. Materials and Methods: The expression of CCR2 was studied using clinical tissue analysis and an in vivo peri‐implantitis model. The role of CCR2 in promoting inflammation and bone resorption in peri‐implantitis was evaluated in Ccr2−/− mice and wild‐type mice. The effect of CVC on peri‐implantitis was evaluated using systemic and local dosage forms. Results: Human peri‐implantitis tissues showed increased CCR2 and CCL2 levels, which were positively correlated with bone loss around the implants. Knocking out Ccr2 in an experimental model of peri‐implantitis resulted in decreased monocyte and macrophage infiltration, reduced pro‐inflammatory cytokine generation and impaired osteoclast activity, leading to reduced inflammation and bone loss around the implants. Treatment with CVC ameliorated bone loss in experimental peri‐implantitis. Conclusions: CCR2 may be a potential target for peri‐implantitis treatment by harnessing the immune‐inflammatory response to modulate the local inflammation and osteoclast activity. [ABSTRACT FROM AUTHOR]