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Integrin α9β1 is known to stabilize leukocyte adhesion to the activated endothelium. We determined the role of myeloid cell α9β1 in early atherosclerosis in two models: α9Mye-KOApoe−/− or the Ldlr−/− mice transplanted with bone marrow (BM) from α9Mye-KO mice fed a high-fat "Western" diet for 4 wk. α9Mye-KOApoe−/− mice exhibited reduced early lesions in the aortae and aortic sinuses (P < 0.05 vs α9WT Apoe−/− mice). Similar results were obtained in α9Mye-KO BM→Ldlr−/− mice (P < 0.05 vs α9WT BM→Ldlr−/− mice). Reduced early atherosclerosis in α9Mye-KOApoe−/− mice was associated with decreased neutrophil and neutrophil extracellular traps (NETs) content in the aortic lesions (P < 0.05 vs α9WTApoe−/−). Vascular cell adhesion molecule-1-stimulated neutrophils from α9Mye-KO mice exhibited reduced adhesion, transmigration, and NETs formation (NETosis) (P < 0.05 vs α9WT neutrophils). Reduced NETosis was associated with decreased extracellular signal-regulated kinase phosphorylation, peptidyl arginine deiminase 4, and citrullinated histone H3 expression. In summary, genetic ablation of myeloid cell-specific α9 reduces early atherosclerosis, most likely by reducing neutrophil adhesion, transmigration, and NETosis. [ABSTRACT FROM AUTHOR]

Neutrophils and eosinophils share common hematopoietic precursors and usually diverge into distinct lineages with unique markers before being released from their hematopoietic site, which is the bone marrow (BM). However, previous studies identified an immature Ly6g(+) Il-5Rα(+) neutrophil population in mouse BM, expressing both neutrophil and eosinophil markers suggesting hematopoietic flexibility. Moreover, others have reported neutrophil populations expressing eosinophil-specific cell surface markers in tissues and altered disease states, confusing the field regarding eosinophil origins, function, and classification. Despite these reports, it is still unclear whether hematopoietic flexibility exists in human granulocytes. To answer this, we utilized single-cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing to profile human BM and circulating neutrophils and eosinophils at different stages of differentiation and determine whether neutrophil plasticity plays role in asthmatic inflammation. We show that immature metamyelocyte neutrophils in humans expand during severe asthmatic inflammation and express both neutrophil and eosinophil markers. We also show an increase in trilobed eosinophils with mixed neutrophil and eosinophil markers in allergic asthma and that interleukin-5 promotes differentiation of immature blood neutrophils into trilobed eosinophilic phenotypes, suggesting a mechanism of emergency granulopoiesis to promote myeloid inflammatory or remodeling response in patients with chronic asthma. By providing insights into unexpectedly flexible granulocyte biology and demonstrating emergency hematopoiesis in asthma, our results highlight the importance of granulocyte plasticity in eosinophil development and allergic diseases. [ABSTRACT FROM AUTHOR]

Neutrophils are essential cells involved in inflammation. However, the specific mechanism of neutrophil chemotaxis induced by Treponema pallidum remains unknown. In this study, human umbilical vein endothelial cells (HUVECs) were utilized as target cells to investigate the expression levels of chemokines when stimulated with different concentrations of Tp0768 (also known as TpN44.5 or TmpA, a T. pallidum infection dependent antigen). The results indicated that Tp0768 treatment enhanced neutrophil chemotaxis in HUVECs, which was closely associated with the expression levels of CXCL1, CXCL2, and CXCL8 (also known as interleukin-8). At the same time, the results show that the Toll-like receptor 2 (TLR2) signaling pathway is activated and that endoplasmic reticulum (ER) stress occurs. Furthermore, the findings revealed that the use of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and immunoglobulin-regulated enhancer 1 (IRE1) inhibitors reduced the expression levels of CXCL1, CXCL2, and CXCL8. Additionally, inhibiting TLR2 significantly decreased the expression levels of ER stress–related proteins (PERK and IRE1), CXCL1, CXCL2, and CXCL8. Consequently, neutrophil chemotaxis was significantly inhibited after treatment with TLR2, PERK, and IRE1 inhibitors. These findings shed light on the role of Tp0768 in enhancing neutrophil chemotaxis in endothelial cells, providing a foundation for further exploration of syphilis pathogenesis and offering a new direction for the diagnosis and treatment of T. pallidum infection. [ABSTRACT FROM AUTHOR]

Objective: To investigate the inhibitory effect of Celastrus orbiculatus extracts (COE) on the proliferation of lymphoma cells and the immune regulation ability on inflammation and thrombophilia in vivo. Methods: The 38B9 lymphoma cells were treated with COE (160 µ g/mL) and CTX (25 µ mol/L). The apoptosis rate and cell cycle of each group were detected by flow cytometry. The secretion of inflammatory factors, including interleukin (IL)-6, IL-10, and tumor necrosis factor α (TNF-α), in cell supernatant was detected by enzyme-linked immunosorbent assay (ELISA). In vivo, BALB/c mice were subcutaneously injected with 38B9 lymphoma cells to establish lymphoma model. COE (3 mg·kg−1·d−1) and CTX (40 mg·kg−1·d−1) were administered to the model mice, respectively. The expression of plasma inflammatory factors (IL-6, IL-10 and TNF-α) and thrombus indexes, including D-dimer (D-D), von Willebrand factor (vWF) and tissue factor (TF), were detected by ELISA before tumor bearing (1 d), after tumor formation (14 d) and after intervention (21 d). PicoGreen dsDNA was used to detect the level of serum neutrophil extracellular traps (NETs). Flow cytometry was used to detect the expression of platelet activation marker calcium-dependent lectin-like receptor 2 (CLEC-2). The tumor growth and survival of mice were recorded. Results: The 38B9 lymphoma cells were apoptotic after the intervention of COE and CTX. The ratio of G2-M phase cells decreased in COE intervented cells compared with the control cells (P<0.05), and S phase cells decreased in CTX intervented cells (P<0.05). Also, the secretion level of IL-6 was significantly reduced after COE or CTX intervention (P<0.05), and IL-10 was significantly increased (P<0.05). Furthermore, the tumor mass was reduced, and the median survival time was longer in COE and CTX intervented tumor-bearing mice than in non-intervented mice. The significantly lower levels of TNF-α, IL-6, NETs, TF, DD and CLEC-2, as well as higher IL-10 were observed in COE and CTX treatment mice in comparision with the control mice (P<0.05). Conclusion: COE has a mild and stable anti-tumor effect, which can reduce the secretion of inflammatory factors by lymphoma cells and regulate thrombophilic state caused by tumor inflammatory microenvironment. [ABSTRACT FROM AUTHOR]

The role of neutrophils in host defense involves several cell processes including phagocytosis, degranulation of antimicrobial proteins, and the release of neutrophil extracellular traps (NETs). In turn, dysregulated cell activity is associated with the pathogenesis of airway and rheumatic diseases, in which neutrophil-derived enzymes including peptidyl-arginine deiminases (PADs) play a role. Known physiological functions of PADs in neutrophils are limited to the activity of PAD isotype 4 in histone citrullination in NET formation. The aim of this study was to extend our knowledge on the role of PADs in neutrophils and, specifically, bacterial killing within the confines of the phagocytic vacuole. Human neutrophils were fractionated by sucrose gradient ultracentrifuge and PADs localized in subcellular compartments by Western blot analysis. Direct interaction of PADs with Pseudomonas aeruginosa (P. aeruginosa) was assessed by flow cytometry and Western blot overlay. The participation of neutrophil PAD2 and PAD4 in killing of P. aeruginosa was assessed by inclusion of PAD-specific inhibitors. In vitro, bactericidal activity of recombinant human PAD2 or PAD4 enzymes against P. aeruginosa was determined by enumeration of colony-forming units (CFU). Together with neutrophil elastase (NE), PAD2 and PAD4 were localized to primary granules and, following activation with particulate stimuli, were degranulated in to the phagocytic vacuole. In vitro, PAD2 and PAD4 bound P. aeruginosa (p = 0.04) and significantly reduced bacterial survival to 49.1 ± 17.0 (p < 0.0001) and 48.5 ± 13.9% (p < 0.0001), respectively. Higher antibacterial activity was observed at neutral pH levels with the maximum toxicity at pH 6.5 and pH 7.5, comparable to the effects of neutrophil bactericidal permeability increasing protein. In phagosomal killing assays, inclusion of the PAD2 inhibitor, AFM-30a, or PAD4 inhibitor, GSK484, significantly increased survival of P. aeruginosa (AFM-30a, p = 0.05; and GSK484, p = 0.0079). Results indicate that PAD2 and PAD4 possess antimicrobial activity and are directly involved in the neutrophil antimicrobial processes. This study supports further research into the development of PAD-based antimicrobials. [ABSTRACT FROM AUTHOR]

Pulmonary melioidosis is a severe tropical infection caused by Burkholderia pseudomallei and is associated with high mortality, despite early antibiotic treatment. γδ T cells have been increasingly implicated as drivers of the host neutrophil response during bacterial pneumonia, but their role in pulmonary melioidosis is unknown. Here, we report that in patients with melioidosis, a lower peripheral blood γδ T-cell concentration is associated with higher mortality, even when adjusting for severity of illness. γδ T cells were also enriched in the lung and protected against mortality in a mouse model of pulmonary melioidosis. γδ T-cell deficiency in infected mice induced an early recruitment of neutrophils to the lung, independent of bacterial burden. Subsequently, γδ T-cell deficiency resulted in increased neutrophil-associated inflammation in the lung as well as impaired bacterial clearance. In addition, γδ T cells influenced neutrophil function and subset diversity in the lung after infection. Our results indicate that γδ T cells serve a novel protective role in the lung during severe bacterial pneumonia by regulating excessive neutrophil-associated inflammation. [ABSTRACT FROM AUTHOR]

Autologous transplantation remains the standard of care for eligible multiple myeloma (MM) patients, yet optimal CD34+ cell dose remains unclear. We conducted a retrospective study on MM patients undergoing upfront transplant between 2005 and 2021 and divided them into low (≤2.5 × 106 cells/kg) and high (>2.5 × 106 cells/kg) CD34+ dose groups. We included 2479 patients, 95 in the low CD34+ group and 2384 in the high CD34+ group. Patients in the low CD34+ group were older (63.2 vs 61.1 years, p = 0.013), more often had R-ISS III (19% vs 9%, p = 0.014), received plerixafor (60% vs 35%, p < 0.001) and transplanted after 2009 (88% vs 80%, p = 0.047). Time to neutrophil and platelet recovery was longer in the low CD34+ group. Median PFS and OS were lower in the low CD34+ group (31.6 vs. 43.6 months, p = 0.011 and 76.4 vs. 108.2 months, p < 0.001, respectively). Evaluation of incrementally higher CD34+ dose did not show significant improvement in survival at thresholds >2.5 × 106 cells/kg. Multivariable analysis affirmed that CD34+ >2.5 × 106 cells/kg was associated with better PFS (HR 0.71, p = 0.008) and OS (0.59, p < 0.001). After propensity score matching, a CD34+ dose >2.5 × 106 cells/kg remained a predictor of better OS (0.42, p < 0.001). In conclusion, CD34+ dose >2.5 × 106 cells/kg was associated with improved survival, without any additional benefit at incrementally higher doses. [ABSTRACT FROM AUTHOR]

Background: Neutrophils have long been consistently adjudged to hold a dominant position in acute inflammation, which once led people to undervalue their role in chronic malignancy. It is now acknowledged that neutrophils also infiltrate into the tumor microenvironment in substantial quantities and form a highly abundant immune population within the tumor, known as tumor-associated neutrophils (TANs). There has been a surge of interest in researching the eminent heterogeneity and plasticity of TANs in recent years, and scholars increasingly cotton on to the multifaceted functions of TANs so that strenuous endeavors have been devoted to enunciating their potential as therapeutic targets. Yet it remains much left to translate TAN-targeted immunotherapies into clinical practice. Therefore, there is great significance to comprehensively appraise the research status, focal point, and evolution trend of TAN by using bibliometric analysis. Methods: Publications related to TAN research from 2000 to 2024 are extracted from the Web of Science Core Collection. Bibliometric analysis and visualization were performed by tools encompassing Microsoft Excel, VOSviewer, CiteSpace, R-bibliometrix, and so on. Results: The bibliometric analysis included a total of 788 publications authored by 5291 scholars affiliated with 1000 institutions across 58 countries/regions, with relevant articles published in 324 journals. Despite China’s maximum quantity of publications and top 10 institutions, the United States is the leading country with the most high-quality publications and is also the global cooperation center. FRONTIERS IN IMMUNOLOGY published the most papers, whereas CANCER RESEARCH is the highest co-cited journal. Israeli professor Fridlender, Zvi G. is the founder, pioneer, and cultivator with the highest citation counts and H-index in the TAN area. Our analysis prefigures the future trajectories: TAN heterogeneity, neutrophil extracellular trap, the crosstalk between TANs and immunocytes, and immunotherapy will likely be the focus of future research. Conclusion: A comprehensive bibliometric and visual analysis is first performed to map the current landscape and intellectual structure of TAN, which proffers fresh perspectives for further research. The accurate identification of distinct TAN subpopulations and the precise targeting of key pro-tumor/anti-tumor subpopulations hold immense potential to develop into a TAN-targeted immunotherapy. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Materials and Methods Results Conclusions VECs play a crucial role in regulating the function of neutrophils, which is essential for immune responses and inflammation. As stretch‐sensitive cells, VECs sense mechanical stretch through surface mechanoreceptors, converting external mechanical stimuli into biochemical signals. This study aimed to explore the molecular mechanisms underlying the regulation of neutrophil behavior by stretched VECs.The key cytokine‐inducing neutrophil N2 polarization in the conditioned medium from stretched vascular endothelial cells (CM‐stretch) was validated through multifactorial matrix and flow cytometry. Additionally, the molecular mechanism underlying the response of vascular endothelial cells to stretch was systematically verified through layer‐by‐layer analysis using WB.IL13, not IL4, was ultimately identified as a key cytokine‐inducing neutrophil N2 polarization in CM‐stretch. Inhibition of the transient receptor potential channel (TRPC1) and siRNA‐mediated knockdown of TRPC1 both significantly decreased IL13 production. Furthermore, neutralizing IL13 in the CM‐stretch or inhibiting STAT3 phosphorylation inhibited neutrophil N2 polarization, as evidenced by reduced CD206 and VEGFA expression.These results demonstrate that stretched VECs initiate a signaling cascade that induces neutrophil N2 polarization through the TRPC1‐IL13‐STAT3 axis, suggesting that mechanical stretching of VECs could shift neutrophil function from a pro‐inflammatory to a more regulatory and healing role. [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]

The article explores the potential of cell population data (CPD) as a diagnostic tool for distinguishing between venous thrombo-embolism (VTE), superficial vein thrombosis (SVT), and erysipelas. By analyzing CPD parameters in patients with these conditions, the study found differences in the intensity and type of cellular inflammation, with erysipelas showing more intense inflammation compared to DVT. The research suggests that CPD could be a promising tool for diagnosing VTE, but larger studies are needed to evaluate its true value in clinical practice. [Extracted from the article]

During inflammation, human neutrophils engage b2-integrins to migrate from the blood circulation to inflammatory sites with high cytokine but low oxygen concentrations. We tested the hypothesis that the inhibition of prolyl hydroxylase domain-containing enzymes (PHDs), cytokines, and b2-integrins cooperates in HIF pathway activation in neutrophils. Using either the PHD inhibitor roxadustat (ROX) (pseudohypoxia) or normobaric hypoxia to stabilize HIF, we observed HIF1a protein accumulation in adherent neutrophils. Several inflammatory mediators did not induce HIF1a protein but provided additive or even synergistic signals (e.g., GM-CSF) under pseudohypoxic and hypoxic conditions. Importantly, and in contrast to adherent neutrophils, HIF1a protein expression was not detected in strictly suspended neutrophils despite PHD enzyme inhibition and the presence of inflammatory mediators. Blocking b2- integrins in adherent and activating b2-integrins in suspension neutrophils established the indispensability of b2-integrins for increasing HIF1a protein. Using GM-CSF as an example, increased HIF1a mRNA transcription via JAK2- STAT3 was necessary but not sufficient for HIF1a protein upregulation. Importantly, we found that b2-integrins led to HIF1a mRNA translation through the phosphorylation of the essential translation initiation factors eIF4E and 4EBP1. Finally, pseudohypoxic and hypoxic conditions inducing HIF1a consistently delayed apoptosis in adherent neutrophils on fibronectin under low serum concentrations. Pharmacological HIF1a inhibition reversed delayed apoptosis, supporting the importance of this pathway for neutrophil survival under conditions mimicking extravascular sites. We describe a novel b2-integrincontrolled mechanism of HIF1a stabilization in human neutrophils. Conceivably, this mechanism restricts HIF1a activation in response to hypoxia and pharmacological PHD enzyme inhibitors to neutrophils migrating toward inflammatory sites. [ABSTRACT FROM AUTHOR]

In patients with sepsis, neutrophil apoptosis tends to be inversely proportional to the severity of sepsis, but its mechanism is not yet clear. This study aimed to explore the mechanism of fatty acid binding protein 4 (FABP4) regulating neutrophil apoptosis through combined analysis of gut microbiota and short-chain fatty acids (SCFAs) metabolism. First, neutrophils from bronchoalveolar lavage fluid (BALF) of patients with sepsis-induced acute respiratory distress syndrome (ARDS) were purified and isolated RNA was applied for sequencing. Then, the cecal ligation and puncture (CLP) method was applied to induce the mouse sepsis model. After intervention with differential SCFAs sodium acetate, neutrophil apoptosis and FABP4 expression were further analyzed. Then, FABP4 inhibitor BMS309403 was used to treat neutrophils. We found CLP group had increased lung injury score, lung tissue wet/dry ratio, lung vascular permeability, and inflammatory factors IL-1β, TNF-α, IL-6, IFN-γ, and CCL3 levels in both bronchoalveolar lavage fluid and lung tissue. Additionally, FABP4 was lower in neutrophils of ARDS patients and mice. Meanwhile, CLP-induced dysbiosis of gut microbiota and changes in SCFAs levels were observed. Further verification showed that acetic acids reduced neutrophil apoptosis and FABP4 expression via FFAR2. Besides, FABP4 affected neutrophil apoptosis through endoplasmic reticulum (ER) stress, and neutrophil depletion alleviated the promotion of ARDS development by BMS309403. Moreover, FABP4 in neutrophils regulated the injury of RLE-6TN through inflammatory factors. In conclusion, FABP4 affected by gut microbiota-derived SCFAs delayed neutrophil apoptosis through ER stress, leading to increased inflammatory factors mediating lung epithelial cell damage. [ABSTRACT FROM AUTHOR]

The overactivated immune cells in the infectious lesion may lead to irreversible organ damages under severe infections. However, clinically used immunosuppressive anti‐inflammatory drugs will usually disturb immune homeostasis and conversely increase the risk of infections. Regulating the balance between anti‐inflammation and anti‐infection is thus critical in treating certain infectious diseases. Herein, considering that hydrogen peroxide (H2O2), myeloperoxidase (MPO), and neutrophils are upregulated in the inflammatory microenvironment and closely related to the severity of appendectomy patients, an inflammatory‐microenvironment‐responsive nanomedicine is designed by using poly(lactic‐co‐glycolic) acid (PLGA) nanoparticles to load chlorine E6 (Ce6), a photosensitizer, and luminal (Lum), a chemiluminescent agent. The obtained Lum/Ce6@PLGA nanoparticles, being non‐toxic within normal physiological environment, can generate cytotoxic single oxygen via bioluminescence resonance energy transfer (BRET) in the inflammatory microenvironment with upregulated H2O2 and MPO, simultaneously killing pathogens and excessive inflammatory immune cells in the lesion, without disturbing immune homeostasis. As evidenced in various clinically relevant bacterial infection models and virus‐induced pneumonia, Lum/Ce6@PLGA nanoparticles appeared to be rather effective in controlling both infection and inflammation, resulting in significantly improved animal survival. Therefore, the BRET‐based nanoparticles by simultaneously controlling infections and inflammation may be promising nano‐therapeutics for treatment of severe infectious diseases. [ABSTRACT FROM AUTHOR]

Fusobacterium nucleatum as a Gram-negative anaerobe plays a key bridging role in oral biofilms. It is involved in periodontal and extraoral diseases, the most prominent being colorectal cancer. Five subspecies are recognised: animalis, fusiforme, nucleatum, polymorphum and vincentii. Subspecies interact with neutrophils constantly patrolling tissues to remove microbial intruders. Neutrophil antimicrobial activities include generation of reactive oxygen species (ROS), formation of neutrophil extracellular traps (NETs) and release of cytokines and neutrophil enzymes. Subspecies-specific differences in immunogenicity have previously been observed in a neutrophil-like cell line but were not investigated in human neutrophils. Additionally, neutrophil responses to planktonic and biofilm-grown F. nucleatum have not been studied to date. The aims of this study were to compare the immunogenicity of planktonic and biofilm-grown F. nucleatum and to investigate potential differences in human neutrophil responses when stimulated with individual F. nucleatum subspecies. Human neutrophils isolated from peripheral blood were stimulated with planktonic and biofilm-grown F. nucleatum subspecies. Generation of ROS and NET formation were quantified by luminescence and fluorescence assays, respectively. Secretion of cytokines (IL-1β, TNF-α, IL-6, IL-8), neutrophil elastase and matrix metalloproteinase-9 was quantified by enzyme-linked immunosorbent assay (ELISA). Neutrophil responses showed biofilm-grown bacteria induced a significantly higher total and intracellular ROS response, as well as shorter time to total ROS release. Biofilm-grown F. nucleatum led to significantly lower IL-1b release. We found significant differences among individual subspecies in terms of total, intracellular ROS and extracellular superoxide. Subspecies polymorphum stimulated the highest mean amount of NET release. Amounts of cytokines released differed significantly among subspecies, while no differences were found in lysosomal enzyme release. Immunogenicity of F. nucleatum in human neutrophils is highly subspecies-specific in vitro with regard to ROS release and cytokine production. Understanding subspecies-specific immunogenicity of F. nucleatum may facilitate the discovery of novel therapeutic targets in F. nucleatum-mediated diseases. [ABSTRACT FROM AUTHOR]

Neutrophils rapidly respond to inflammation resulting from infection, injury, and cancer. Intravital microscopy (IVM) has significantly advanced our understanding of neutrophil behavior, enabling real-time visualization of their migration, interactions with pathogens, and coordination of immune responses. This review delves into the insights provided by IVM studies on neutrophil dynamics in various inflammatory contexts. We also examine the dual role of neutrophils in tumor microenvironments, where they can either facilitate or hinder cancer progression. Finally, we highlight how computational modeling techniques, especially agent-based modeling, complement experimental data by elucidating neutrophil kinetics at the level of individual cells as well as their collective behavior. Understanding the role of neutrophils in health and disease is essential for developing new strategies for combating infection, inflammation and cancer. [ABSTRACT FROM AUTHOR]

Introduction: Ewing Sarcoma (EWS) has been reported in seven children with Down syndrome (DS). To date, a detailed assessment of this solid tumour in DS patients is yet to be made. Methods: Here,we characterise a chemo-resistantmediastinal EWS in a 2-year-old DS child, the youngest ever reported case, by exploiting sequencing approaches. Results: The tumour showed a neuroectodermal development driven by the EWSR1-FLI1 fusion. The inherited myeloperoxidase deficiency of the patient caused failure of neutrophil-mediated cell death and promoted genomic instability. Discussion: In this context, the tumour underwent genome-wide near haploidisation resulting in a massive overexpression of pro-inflammatory cytokines. Recruitment of defective neutrophils fostered rapid evolution of this EWS. [ABSTRACT FROM AUTHOR]

While pre-post differences in immune cell mobilization after acute aerobic exercise are well investigated, less is known about when and to what extent immune cells are mobilized during acute aerobic exercise. This experimental trial aimed to investigate the detailed kinetics of circulating immune cells in twelve healthy adults (n=6 females) who completed a 40-min aerobic exercise bout at 60% of the participantsʼ V̇O2peak on a bicycle ergometer. Cellular inflammation markers and sex-dependent differences in circulating immune cells were analyzed. Blood samples were taken immediately before, after warm-up, during exercise after 5 min, 10 min, 15 min, 30 min, 40 min (cessation), and 60 min post exercise. Significant increases in leukocytes (p<0.001), lymphocytes (p<0.001), neutrophils (p=0.003) and platelets (p=0.047) can be observed after 5 min of exercise. The cellular inflammation markers show significant alterations only post exercise. Significant sex differences were observed for neutrophils (p=0.049) and neutrophil-to-lymphocyte ratio (p=0.007) one hour post exercise. These results indicate that i) leukocytes are already mobilized after 5 min of moderate-to-vigorous aerobic exercise, ii) the magnitude of exercise induced leukocyte mobilization is dependent on exercise duration, iii) integrative cellular inflammation markers are only altered after exercise cessation, and iv) the observed effects might be sex-dependent. [ABSTRACT FROM AUTHOR]

Simple Summary: This study examines the immune differences in follicular lymphoma (FL) and particularly focuses on the transformation into an aggressive disease, a major cause of FL-related deaths. We analyzed gene expression in diagnostic samples from 70 FL patients, categorized as either non-transforming FL (nt-FL) and subsequently transforming FL (st-FL) using NanoString technology. We identified 164 significantly differentially expressed genes between nt-FL and nt-FL samples, with st-FL showing an increased expression of B cell-related and immunosuppressive genes. Particularly, immune cell analysis revealed differences in macrophage and neutrophil fractions between nt-FL and st-FL, with higher levels of these cells linked to shorter transformation-free survival. Meanwhile, tFL samples had fewer T follicular helper cells and more immunosuppressive macrophages and neutrophils. The findings highlight the critical role of the immune microenvironment in FL transformation and patient outcomes. Background: Follicular lymphoma (FL) presents significant clinical heterogeneity, with some patients experiencing transformation into an aggressive disease, a key contributor to FL-related mortality. Based on gene expression profiles, this study aimed to provide insights into immunological differences associated with transformation. Methods: Gene expression analysis using the NanoString nCounter Tumor Signaling 360 Panel was performed on diagnostic lymphoma samples from 70 FL patients diagnosed in the rituximab era, either non-transforming FL (nt-FL, n = 34) or subsequently transforming FL (st-FL, n = 36), with paired high-grade transformed FL (tFL, n = 36) samples available. In silico immunophenotyping was performed to infer immune cell infiltration using the CIBERSORTx algorithm. Results: The gene expression analysis revealed 164 significantly differentially expressed genes, distinguishing st-FL from nt-FL and generally presenting an upregulation of B cell-related genes (CD40, IRF4, RELB), immunosuppressive molecules (IL10, SOCS3), and immune checkpoint molecules (CD276, TIM3). Analysis of immune cell proportions indicated significant differences in infiltrates of M1-like macrophages (p = 0.007) and neutrophils (p = 0.012) in nt-FL versus st-FL samples. Transformation-free survival (TFS) was associated with high numbers of both these cellular subsets (p = 0.006 and 0 = 0.002, respectively). This was even more evident when combined with inferior TFS in lymphomas with high infiltrates of both cell types (p < 0.001). After transformation, tFL samples showed a reduction in T follicular helper cells (p = 0.008) and an increase in immunosuppressive M2-like macrophages and neutrophils (p < 0.001 and p = 0.028, respectively). Conclusion: By elucidating the distinct molecular and immune landscapes of FL at the time of diagnosis and transformation, this study underscores the importance of immune microenvironment in FL transformation and patient outcome. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition of the gut affecting both adults and children. Neutrophil extracellular traps (NETs) are structures released by activated neutrophils, potentially contributing to tissue damage in various diseases. This study aimed to explore the presence and role of NETs in pediatric IBD. We compared intestinal biopsies and peripheral blood from 20 pediatric IBD patients (UC and CD) to controls. Biopsy staining and techniques for neutrophil activation were used to assess neutrophil infiltration and NET formation. We also measured the enzymatic activity of key NET proteins and evaluated NET formation in UC patients in remission. Both UC and CD biopsies showed significantly higher levels of neutrophils and NETs compared to controls (p < 0.01), with UC exhibiting the strongest association. Peripheral blood neutrophils from UC patients at diagnosis displayed increased NET formation compared to controls and CD patients. Interestingly, NET formation normalized in UC patients following remission-inducing treatment. This pilot study suggests a potential role for NETs in pediatric IBD, particularly UC. These findings warrant further investigation into the mechanisms of NET involvement and the potential for targeting NET formation as a therapeutic strategy. [ABSTRACT FROM AUTHOR]

Neutrophil polarization contributes to inflammation and its resolution, but the role of neutrophil polarization in myocardial ischemia/reperfusion (I/R) injury remains unknown. Cardiomyocytes (CMs) participate in cardiac inflammation by secreting extracellular vesicles (EVs). Therefore, we investigated the role of neutrophil polarization in myocardial I/R injury and the mechanism by which CM-derived EVs regulated neutrophil polarization. In the present study, our data showed that N1 neutrophil polarization enlarged cardiac infarct size and exacerbated cardiac dysfunction at the early stage of myocardial I/R. Further, CM-EV-derived miR-9-5p was identified as a mediator inducing neutrophils to the N1 phenotype. Mechanistically, miR-9-5p directly suppressed SOCS5 and SIRT1 expression, resulting in activating JAK2/STAT3 and NF-κB signaling pathways in neutrophils. Importantly, we confirmed that serum EV-derived miR-9-5p levels were independently associated with cardiovascular mortality in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. These findings suggest neutrophil polarization is a promising therapeutic target against myocardial I/R-induced inflammation and injury, and serum EV-derived miR-9-5p is a promising prognostic biomarker for cardiovascular mortality in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. [ABSTRACT FROM AUTHOR]

The development of acute respiratory distress syndrome (ARDS) in sepsis is associated with substantial morbidity and mortality. However, the molecular pathogenesis underlying sepsis‐induced ARDS remains elusive. Neutrophil heterogeneity and dysfunction contribute to uncontrolled inflammation in patients with ARDS. A specific subset of neutrophils undergoing reverse transendothelial migration (rTEM), which is characterized by an activated phenotype, is implicated in the systemic dissemination of inflammation. Using single‐cell RNA sequencing (scRNA‐seq), it identified functionally activated neutrophils exhibiting the rTEM phenotype in the lung of a sepsis mouse model using cecal ligation and puncture. The prevalence of neutrophils with the rTEM phenotype is elevated in the blood of patients with sepsis‐associated ARDS and is positively correlated with disease severity. Mechanically, scRNA‐seq and proteomic analys revealed that inflamed endothelial cell (EC) released extracellular vesicles (EVs) enriched in karyopherin subunit beta‐1 (KPNB1), promoting abluminal‐to‐luminal neutrophil rTEM. Additionally, EC‐derived EVs are elevated and positively correlated with the proportion of rTEM neutrophils in clinical sepsis. Collectively, EC‐derived EV is identified as a critical regulator of neutrophil rTEM, providing insights into the contribution of rTEM neutrophils to sepsis‐associated lung injury. [ABSTRACT FROM AUTHOR]

Epidural fibrosis is a primary contributor to the failure of laminectomy surgeries, leading to the development of failed back surgery syndrome (FBSS). Post-laminectomy, neutrophils infiltrate the surgical site, generating neutrophil extracellular traps (NETs) that contribute to epidural fibrosis. Reactive oxygen species (ROS) play a pivotal role in mediating NETs formation. Molecular hydrogen, recognized for its selective antioxidant properties and biosafety, emerges as a potential therapeutic gas in suppressing epidural fibrosis. In this study, we developed an in-situ hydrogen release hydrogel that inhibits the formation of NETs and mitigates epidural scarring. Biodegradable magnesium (Mg) microspheres served as a hydrogen source, coated with PLGA to regulate hydrogen release. These microspheres (Mg@PLGA) were then incorporated into a PLGA-PEG-PLGA thermosensitive hydrogel (Mg@PLGA@Gel), providing a surgical implant for sustained, long-term hydrogen release. In vitro experiments confirmed the biocompatibility of the system, demonstrating that hydrogen produced by Mg@PLGA effectively neutralizes neutrophil intracellular ROS and inhibits NETs formation. Histological analyses, including H&E staining, MRI, Masson staining, and immunohistochemistry, collectively indicate that Mg@PLGA@Gel is biocompatible and effectively inhibits epidural fibrosis post-laminectomy. Furthermore, Mg@PLGA@Gel inhibits ROS accumulation and NETs formation at the surgical site. These findings suggest that Mg@PLGA@Gel ensures continuous, therapeutic hydrogen concentration, providing relief from epidural fibrosis in a laminectomy mouse model. • The hydrogen-releasing hydrogel combines the therapeutic effects of a physical barrier with immunomodulation. • In situ-generated molecular hydrogen scavenges ROS caused by surgical stress and suppresses NETs formation. • The hydrogen-releasing hydrogel is demonstrated to exhibit high biocompatibility and inhibit epidural scar formation in vivo. [Display omitted] [ABSTRACT FROM AUTHOR]

Post-tuberculosis (post-TB) lung disease is increasingly recognized as a major contributor to the global burden of chronic lung disease, with recent estimates indicating that over half of TB survivors have impaired lung function after successful completion of TB treatment. However, the pathologic mechanisms that contribute to post-TB lung disease are not well understood, thus limiting the development of therapeutic interventions to improve long-term outcomes after TB. This report summarizes the work of the Pathogenesis and Risk Factors Committee for the Second International Post-Tuberculosis Symposium, which took place in Stellenbosch, South Africa, in April 2023. The committee first identified six areas with high translational potential: 1) tissue matrix destruction, including the role of matrix metalloproteinase dysregulation and neutrophil activity; 2) fibroblasts and profibrotic activity; 3) granuloma fate and cell death pathways; 4) mycobacterial factors, including pathogen burden; 5) animal models; and 6) the impact of key clinical risk factors, including HIV, diabetes, smoking, malnutrition, and alcohol. We share the key findings from a literature review of those areas, highlighting knowledge gaps and areas where further research is needed. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) is a malignancy with significant immunosuppressive properties and limited immune activation. This immunosuppression is linked to reduced cytotoxic T cell activity, impaired antigen presentation, and elevated levels of immunosuppressive cytokines and immune checkpoint molecules. Studies demonstrate that cytotoxic CD8+ T cell infiltration correlates with improved survival, while increased regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) are associated with worse outcomes and therapeutic resistance. Th1 cells are beneficial, whereas Th17 cells, producing interleukin-17 (IL-17), contribute to tumor progression. Tumor-associated neutrophils (TANs) and immune checkpoint molecules, such as PD-1/PD-L1 and T cell immunoglobulin-3 (TIM-3) are also linked to advanced stages of PCa. Chemotherapy holds promise in converting the “cold” tumor microenvironment (TME) to a “hot” one by depleting immunosuppressive cells and enhancing tumor immunogenicity. Summary: This comprehensive review examines the immune microenvironment in PCa, focusing on the intricate interactions between immune and tumor cells in the TME. It highlights how TAMs, Tregs, cytotoxic T cells, and other immune cell types contribute to tumor progression or suppression and how PCa’s low immunogenicity complicates immunotherapy. Key Messages: The infiltration of cytotoxic CD8+ T cells and Th1 cells correlates with better outcomes, while elevated T regs and TAMs promote tumor growth, metastasis, and resistance. TANs and natural killer (NK) cells exhibit dual roles, with higher NK cell levels linked to better prognoses. Immune checkpoint molecules like PD-1, PD-L1, and TIM-3 are associated with advanced disease. Chemotherapy can improve tumor immunogenicity by depleting T regs and myeloid-derived suppressor cells, offering therapeutic promise. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) effectively kills cancer cells and initiates immune responses that promote anticancer effects locally and systemically. Primarily developed for local and regional cancers, the potential of PDT for systemic antitumor effects [in situ photo‐vaccination (ISPV)] remains underexplored. This study investigates: (1) the comparative effectiveness of paclitaxel (PTX) prodrug [Pc‐(L‐PTX)2] for PDT and site‐specific PTX effects versus its pseudo‐prodrug [Pc‐(NCL‐PTX)2] for PDT combined with checkpoint inhibitors; (2) mechanisms driving systemic antitumor effects; and (3) the prophylactic impact on preventing cancer recurrence. A bilateral tumor model was established in BALB/c mice through subcutaneous injection of CT26 cells. Mice received the PTX prodrug (0.5 μmole kg−1, i.v.), and tumors were treated with a 690‐nm laser (75 mW cm−2 for 30 min, drug‐light interval 0.5 h, light does 135 J cm−1), followed by anti‐CTLA‐4 (100 μg dose−1, i.p.) on days 1, 4, and 7. Notable enhancement in both local and systemic antitumor effectiveness was observed with [Pc‐(L‐PTX)2] compared to [Pc‐(NCL‐PTX)2] with checkpoint inhibitor. Immune cell depletion and immunohistochemistry confirmed neutrophils and CD8+ T cells are effectors for systemic antitumor effects. Treatment‐induced immune memory resisted newly rechallenged CT26, showcasing prophylactic benefits. ISPV with a PTX prodrug and anti‐CTLA‐4 is a promising approach for treating metastatic cancers and preventing recurrence. [ABSTRACT FROM AUTHOR]

Background: Severe adenovirus pneumonia in children has a high mortality rate, but research on risk prediction models is lacking. Such models are essential as they allow individualized predictions and assess whether children will likely progress to severe disease. Methods: A retrospective analysis was performed on children with adenovirus pneumonia who were hospitalized at the Children's Hospital of Nanjing Medical University from January 2017 to March 2024. The patients were grouped according to clinical factors, and the groups were compared using Ridge regression and multiple logistic regression to identify risk factors associated with severe adenovirus pneumonia. A prediction model was constructed, and its value in clinical application was evaluated. Results: 699 patients were included in the study, with 284 in the severe group and 415 in the general group. Through the screening of 44 variables, the final risk factors for severe adenovirus pneumonia in children as the levels of neutrophils (OR = 1.086, 95% CI: 1.054‒1.119, P < 0.001), D-dimer (OR = 1.005, 95% CI: 1.003‒1.007, P < 0.001), fibrinogen degradation products (OR = 1.341, 95% CI: 1.034‒1.738, P = 0.027), B cells (OR = 1.076, 95%CI: 1.046‒1.107, P < 0.001), and lactate dehydrogenase (OR = 1.008, 95% CI: 1.005‒1.011, P < 0.001). The value of the area under the receiver operating characteristic curve was 0.974, the 95% CI was 0.963–0.985, and the P-value of the Hosmer-Lemeshow test was 0.547 (P > 0.05), indicating that the model had strong predictive power. Conclusion: In this study, the clinical variables of children with adenovirus pneumonia were retrospectively analyzed to identify risk factors for severe disease. A prediction model for severe disease was constructed and evaluated, showing good application value. [ABSTRACT FROM AUTHOR]

As frontline cells, the precise recruitment of neutrophils is crucial for resolving inflammation and maintaining the homeostasis of the organism. Increasing evidence suggests the pivotal role of neutrophil chemotaxis in cancer progression and metastasis. Here, we collected clinical data and peripheral blood samples from patients with tumours to examine the alterations in the neutrophil quantity and chemotactic function using the Cell Chemotaxis Analysis Platform (CCAP). Transcriptome sequencing data of pan-cancer were obtained from The Cancer Genome Atlas (TCGA). Using the least absolute shrinkage and selection operator (LASSO) Cox regression model, we selected a total of 29 genes from 155 neutrophil- and chemotaxis-related genes to construct the ChemoScore model. Meanwhile, nomogram-based comprehensive model was established for clinical application. Furthermore, immunofluorescence (IF) staining was employed to assess the relationship between the neutrophils infiltrating and the survival outcomes of tumours. In this observational study, the chemotactic function of neutrophils was notably diminished in patients. The establishment and validation of ChemoScore suggested neutrophil chemotaxis to be a risk factor in most tumours, whereby higher scores were associated with poorer survival outcomes and were correlated with various immune cells and malignant biological processes. Moreover, IF staining of tumour tissue substantiated the adverse correlation between neutrophil infiltration and the survival of patients with lung adenocarcinoma (P = 0.0002) and colon adenocarcinoma (P = 0.0472). Taken together, patients with tumours demonstrated a decrease in chemotactic function. ChemoScore potentially prognosticates the survival of patients with tumours. Neutrophil chemotaxis provides novel directions and theoretical foundations for anti-tumour treatment. [ABSTRACT FROM AUTHOR]

Summary We investigated the effect of Ropeginterferon alfa‐2b (Ropeg) versus phlebotomy‐only (Phl‐O) on the neutrophil‐to‐lymphocyte ratio (NLR) in 126 patients randomized in the low‐polycythaemia vera (PV) phase II trial. Patients with a baseline NLR ≥3.5 vs. <3.5 had a longer history of PV, were more likely to have splenomegaly, higher JAK2V617F variant allele frequency (VAF) (56% vs. 20% p = 0.001) and more proliferative disease. Ropeg was superior to Phl‐O in reducing NLR (p = 0.008), and the reduction was strongly influenced by the reduction in neutrophils and less by a change in lymphocytes (−59% and −14% respectively). This effect was associated with the achievement of the low‐PV primary end‐point (p = 0.021), symptom reduction and reduction in JAK2 VAF. Interestingly, the reduction in JAK2 VAF from baseline was linearly associated with the reduction in NLR. Patients who failed Phl‐O at 12 months had characteristics that distinguished them from responders, including very high NLR and resistance to cross‐over to 100 μg Ropeg every 2 weeks suggesting higher escalated doses of Ropeg. In conclusion, the study provides evidence that NLR can serve as a valuable biomarker to assess and guide treatment with Ropeg in the early stage of low‐risk PV patients. [ABSTRACT FROM AUTHOR]

Neutrophils collectively migrate to sites of injury and infection. How these swarms are coordinated to ensure the proper level of recruitment is unknown. Using an ex vivo model of infection, we show that human neutrophil swarming is organized by multiple pulsatile chemoattractant waves. These waves propagate through active relay in which stimulated neutrophils trigger their neighbors to release additional swarming cues. Unlike canonical active relays, we find these waves to be self-terminating, limiting the spatial range of cell recruitment. We identify an NADPH-oxidase-based negative feedback loop that is needed for this self-terminating behavior. We observe near-constant levels of neutrophil recruitment over a wide range of starting conditions, revealing surprising robustness in the swarming process. This homeostatic control is achieved by larger and more numerous swarming waves at lower cell densities. We link defective wave termination to a broken recruitment homeostat in the context of human chronic granulomatous disease. [Display omitted] • Neutrophil swarming is organized by pulsatile, self-extinguishing waves of LTB4 • NADPH-oxidase activation is critical for relay wave self-extinction • Neutrophils adjust the size and number of waves to homeostatically control recruitment • Chronic granulomatosis disease neutrophils generate undamped relay waves that do not extinguish Strickland et al. find that human neutrophils organize pulsatile, self-extinguishing waves of leukotriene B4 to ensure robust homeostatic recruitment. Self-extinguishing waves are dependent on the activity of NADPH oxidase, and deficiency in this pathway leads to a reduced ability to extinguish relay waves. [ABSTRACT FROM AUTHOR]

Although the role of low-density granulocytes (LDGs), neutrophils in the peripheral blood mononuclear cell (PBMC) fraction, and neutrophil extracellular traps (NETs) in assessing lupus disease severity is acknowledged, data specific to childhood-onset lupus remains scarce. This study analyzed 46 patients with childhood-onset systemic lupus erythematosus (82.6% females, mean age 14.5 ± 0.3 years), including 26 cases with normal complement levels and 20 with low complement levels, along with 20 healthy adult volunteers. Key parameters that distinguished healthy volunteers from lupus patients and differentiated between lupus patients with low and normal complement were serum interferon (IFN)-α, serum citrullinated histone 3 (CitH3), and extracellular traps (ETs) in LDGs. However, NETs (assessed by nuclear staining morphology), LDG abundance, and other parameters (such as endotoxemia, cytokines, and double-stranded (ds) DNA) did not show such differentiation. When lipopolysaccharide (LPS) was administered to LDGs in the PBMC fraction, it induced ETs in both low and normal complement groups, indicating the inducible nature of ETs. In adult healthy volunteers, activation by recombinant IFN-α or dsDNA in isolated neutrophils induced LDGs and NETs (identified using immunofluorescent staining for CitH3, myeloperoxidase, and neutrophil elastase) at 45 min and 3 h post-stimulation, respectively. Additionally, approximately half of the LDGs underwent late apoptosis at 3 h post-stimulation, as determined by flow cytometry analysis. Activation by IFN-α or dsDNA in LDGs also led to a more pronounced expression of CD66b, an adhesion molecule, compared to regular-density neutrophils, suggesting higher activity in LDGs. In conclusion, IFN-α and/or dsDNA in serum may transform regular-density neutrophils into LDGs before progressing to NETosis and apoptosis, potentially exacerbating lupus severity through cell death-induced self-antigens. Therefore, LDGs and ETs in LDGs could provide deeper insights into the pathophysiology of childhood-onset lupus. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb) infection induces a marked influx of neutrophils into the lungs, which intensifies the severity of tuberculosis (TB). The metabolic state of neutrophils significantly influences their functional response during inflammation and interaction with bacterial pathogens. However, the effect of Mtb infection on neutrophil metabolism and its consequent role in TB pathogenesis remain unclear. In this study, we examined the contribution of glycolysis and fatty acid metabolism on neutrophil responses to Mtb HN878 infection using ex-vivo assays and murine infection models. We discover that blocking glycolysis aggravates TB pathology, whereas inhibiting fatty acid oxidation (FAO) yields protective outcomes, including reduced weight loss, immunopathology, and bacterial burden in lung. Intriguingly, FAO inhibition preferentially disrupts the recruitment of a pathogen-permissive immature neutrophil population (Ly6Glo/dim), known to accumulate during TB. Targeting carnitine palmitoyl transferase 1a (Cpt1a)-a crucial enzyme in mitochondrial β-oxidation-either through chemical or genetic methods impairs neutrophils' ability to migrate to infection sites while also enhancing their antimicrobial function. Our findings illuminate the critical influence of neutrophil immunometabolism in TB pathogenesis, suggesting that manipulating fatty acid metabolism presents a novel avenue for host-directed TB therapies by modulating neutrophil functions. Author summary: Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a significant global health issue. Neutrophils, immune cells that rapidly enter the lungs during Mtb infection, contribute both to fighting the infection and exacerbating lung damage. Their metabolic state, especially the way they produce energy, is crucial for their function during TB. However, the specific impact of Mtb on neutrophil metabolism and its role in TB progression has been unclear. In this study, we investigated the roles of glycolysis and fatty acid metabolism in neutrophil responses to Mtb infection. We found that inhibiting glycolysis worsens TB outcomes, while blocking fatty acid oxidation (FAO) provides protection, reducing lung damage, bacterial load, and overall disease severity. Notably, FAO inhibition specifically disrupts the accumulation of an immature neutrophil population that is more susceptible to Mtb, thereby improving infection control. Targeting carnitine palmitoyl transferase 1a (Cpt1a), a key enzyme in fatty acid metabolism, impaired neutrophil migration to infection sites and enhanced their antimicrobial activity. These findings suggest that modulating neutrophil metabolism, particularly through FAO inhibition, could be a promising strategy for developing host-directed TB therapies. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) continues to be a major health concern in today's world. Despite conflictive findings, evidence supports systemic inflammation's impact on CRC patients' survival rates. Therefore, this study aims to assess the prognostic role of the innate immune system in patients with CRC. Method: A total of 449 patients were included, with a 5-year follow-up period, and absolute neutrophil counts and their related ratios were measured. Results: The non-survival group had increased levels of white blood cells, neutrophils (both p<0.001), and monocytes (p=0.038), compared to the survival group, along with other neutrophil-related ratios. We observed increased mortality risk in patients in the highest tertile of white blood cells [HR=1.85 (1.09-3.13), p<0.05], neutrophils [HR=1.78 (95% CI: 1.07-2.96), p<0.05], and monocytes [HR=2.11 (95% CI: 1.22-3.63)], compared to the lowest tertile, after adjusting for all clinicopathological variables. Random forest analysis identified neutrophils as the most crucial variable in predicting survival rates, having an AUC of 0.712, considering all clinicopathological variables. A positive relationship between neutrophil counts and metastasis was observed when neutrophil counts are considered continuous (b=0.92 (0.41), p<0.05) and tumor size (width) when neutrophils were considered as logistic variable (T1 vs T3) [OR=1.42, (95% CI: 1.05-1.98), p<0.05]. Conclusion: This study offers comprehensive insights into the immune factors that impact the prognosis of CRC, emphasizing the need for personalized prognostic tools. [ABSTRACT FROM AUTHOR]

Neutrophils, which originate from the bone marrow and are characterized by a segmented nucleus and a brief lifespan, have a crucial role in the body's defense against infections and acute inflammation. Recent research has uncovered the complex roles of neutrophils as regulators in tumorigenesis, during which neutrophils exhibit a dualistic nature that promotes or inhibits tumor progression. This adaptability is pivotal within the tumor microenvironment (TME). In this review, we provide a comprehensive characterization of neutrophil plasticity and heterogeneity, aiming to illuminate current research findings and discuss potential therapeutic avenues. By delineating the intricate interplay of neutrophils in the TME, this review further underscores the urgent need to understand the dual functions of neutrophils with particular emphasis on the anti-tumor effects to facilitate the development of effective therapeutic strategies against cancer. [ABSTRACT FROM AUTHOR]

Introduction: Abiraterone and enzalutamide are two androgen receptor pathway inhibitors approved, among others, for the treatment of metastatic castration-resistant prostate cancer in adult men whose disease has progressed on or after a docetaxel-based regimen. Although hematological effects, especially neutropenia, are one of the main complications of other oral antineoplastic drugs, these adverse effects are infrequent in the case of androgen receptor pathway inhibitors. Case report: We report the case of a patient diagnosed with metastatic castration-resistant prostate cancer who discontinued an androgen receptor pathway inhibitor due to drug-related grade 4 neutropenia. His control blood counts before enzalutamide starting were normal. After one month of treatment, he developed a grade 4 neutropenia, with complete neutrophil count recovery four weeks later. He underwent a bone marrow aspiration, which revealed normocelullar results, and enzalutamide was restarted. Three weeks later, the treatment was eventually discontinued due to neutropenia reappearance. Neutrophil count recovery was achieved one month later. Then, he started treatment with abiraterone, but two weeks later neutropenia reappeared. Abiraterone was withdrawn, and the patient recovered from neutropenia 2 weeks later. Management and outcomes: This case exposes not only the occurrence of rare toxicity of two individual drugs but also the description of a probable drug-class adverse event not reported before. The patient recovered from neutropenia after the androgen receptor pathway inhibitor was withdrawn, thereby supporting the diagnosis of probable drug-induced neutropenia. Discussion: There is scarce evidence in the literature concerning androgen receptor pathway inhibitor-related neutropenia. However, its life-threatening potential cannot be ignored, so healthcare professionals should be warned of the possibility of the occurrence of such adverse reactions. [ABSTRACT FROM AUTHOR]

Aim: The role of inflammation and immune system pathologies in Adolescent Idiopathic Scoliosis (AIS) has recently been the focus of research. It has been reported that the neutrophil/lymphocyte (NLR), platelet/lymphocyte (PLR) and monocyte/lymphocyte (MLR) ratios may be markers of inflammation severity. In addition, the systemic immune inflammation index (SII), including peripheral neutrophils, lymphocytes, monocytes and platelets, systemic inflammatory response index (SIRI) and systemic inflammation total index (AISI) are also known as inflammation marker indexes. This study aimed to investigate the relationship between NLR, PLR, MLR, SII, SIRI, AISI and Cobb angle in patients with AIS. Materials and Methods: Pediatric patients aged 10-18 years who were requested to undergo scoliosis radiography with a preliminary diagnosis of AIS were retrospectively screened. Cobb angles, neutrophils, lymphocytes, platelets, monocytes, neutrophil percentage, white blood cells (WBC) and hemoglobin values were recorded. The NLR, PLR, MLR, SII, SIRI and AISI values were calculated. The patients were divided into four groups according to their Cobb angle. We examined whether there was a difference between the groups in terms of neutrophil, lymphocyte, platelet, monocyte, neutrophil percentage, WBC, Hemoglobin, NLR, PLR, MLR, SII, SIRI, AISI values. It was examined whether there was a correlation between the Cobb angle and NLR, PLR, MLR, SII, SIRI and AISI in patients diagnosed with scoliosis with a Cobb angle greater than 10°. Results: A significant difference in NLR was observed between groups 2 and 4. A positive correlation was observed between groups 2, 3, and 4 patients with a Cobb angle greater than 0 and NLR; no correlation was observed between PLR, MLR, SII, SIRI and AISI. Conclusion: NLR, which is associated with the severity of inflammation, is a marker that correlates with the scoliosis angle in patients with AIS. Larger-scale studies are needed to elucidate the relationship between AIS and the NLR. [ABSTRACT FROM AUTHOR]

Background/Objectives: Asthma is a chronic inflammatory disorder of the airways affecting over 10% of the global population. It is characterized by airway inflammation, mucus hypersecretion, and bronchial hyperresponsiveness, driven predominantly by type 2 helper T cells (Th2) and type 2 innate lymphoid cells (ILC2s) in a subset of patients. However, a significant portion of asthmatic individuals present with "type 2-low" asthma that is often refractory to standard inhaled corticosteroid (ICS) therapy. Therefore, developing innovative therapeutic strategies has become essential. Recent studies have highlighted cannabidiol (CBD) as a promising anti-inflammatory agent capable of modulating immune responses. This study investigates the therapeutic potential of a high-CBD extract (CBD-X) in asthma. Methods: We evaluated the effects of CBD-X on cells involved in asthma pathogenesis using primary human Th2 cells, neutrophils, and asthma mouse model. Results: Our findings indicate that CBD-X extract inhibits Th2 differentiation and reduces the secretion of IL-5 and IL-13, which are crucial cytokines in asthma. Additionally, CBD-X significantly reduces pro-inflammatory cytokines IL-8 and IL-6 in neutrophils and impairs their migration, a critical step in airway inflammation. In a murine asthma model, CBD-X administration led to marked downregulation of IgE and pro-asthmatic cytokines, along with reduced leukocyte, eosinophil, and neutrophil infiltration in lung tissues. Conclusions: These results suggest that CBD-X extract could offer a novel and complementary approach to managing both type 2-high and type 2-low asthma by targeting key inflammatory pathways and modulating immune cell behavior. [ABSTRACT FROM AUTHOR]

The editorial "Hantavirus Research in Finland" discusses various studies on hantavirus infections conducted in Finland between 2021 and 2022. The research focuses on immune responses, pathogenesis, clinical outcomes, epidemiology, ecology, and treatment of hantavirus infections. Findings include the potential use of neutralizing antibodies as therapy, the association of plasma glucose levels with disease severity, and the successful use of icatibant in severe cases of PUUV infection. The research highlights the importance of continued collaboration between virologists, clinicians, and zoologists in Finland and Sweden to further understand hantavirus infections. [Extracted from the article]

Background: Proteinuria is a key indicator of kidney damage in diabetic nephropathy, and its severity correlates with the progression of the disease. In diabetic patients, it is crucial to identify reliable predictors for proteinuria and its severity for early detection and management of kidney damage. Materials and Methods: This cross-sectional study was conducted from November 16, 2022, to May 20, 2023, on patients with type 2 diabetes mellitus (T2DM) who were outpatients at clinics of Shahid Modarres Hospital, Tehran, Iran. Participants were categorized based on their level of proteinuria during 24-h as follows: group A1 (normal to mildly increased proteinuria), Group A2 (moderately increased proteinuria), and Group A3 (severely increased proteinuria). Then, complete blood cell count and other laboratory parameters, were compared between study groups. Results: In this cross-sectional study, 128 participants, including 53 (41.4%) men and 75 (58.6%) women with T2DM, were enrolled. The mean age of participants was 56.40 ± 13.31 years. Although there were no significant differences between cell count and parameters of three groups, a statistically significant difference was seen in neutrophil-to-lymphocyte ratio (NLR) (1.93 ± 0.76, 2.34 ± 0.93, and 2.73 ± 1.07 in A1, A2, and A3 groups, respectively; P = 0.003). Further analysis showed that NLR was significantly higher in Group A3 compared to A1 (2.73 ± 1.07 vs. 1.93 ± 0.76, respectively; P = 0.006), but there was no significant difference between Groups A3 and A2 (2.73 ± 1.07 vs. 2.34 ± 0.93, respectively; P = 0.482) and between Groups A2 and A1 (2.34 ± 0.93 vs. 1.93 ± 0.76, respectively; P = 0.257). Conclusion: Overall, this study suggests that some routine laboratory parameters may be associated with proteinuria and its severity in patients with T2DM. NLR, in particular, showed this association in our study, promising future studies evaluating this association and whether it can help as a predictor or not. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is globally recognized as the most prevalent and aggressive subtype of non-Hodgkin lymphoma. While conventional treatments are effective initially, the disease can become resistant or relapse over time. This study aimed to examine the differentially expressed genes at the transcriptome level and molecular pathways in DLBCL patients. Methods: This investigation utilized RNA sequencing analysis to compare differentially expressed gene samples from five diffuse large B-cell lymphoma patients with two healthy volunteers. These participants were admitted to UKM Medical Center, Kuala Lumpur between 2019 and 2020. The differentially expressed genes were identified using the DESeq2 R package (version 1.10.1) using a negative binomial distribution model. The obtained P values were corrected with the Benjamin and Hochberg method and identified using a False Discovery Rate threshold of <0.05, with log2 fold change (FC) of ≥2 or ≤-2. Results: Results showed 73 differentially expressed genes between the two groups, among which 70 genes were downregulated, and three genes were upregulated. The differentially expressed genes analyzed with the Reactome pathway were significantly associated with the downregulation of antimicrobial humoral response (P<0.001), neutrophil degranulation (P<0.001), chemokine receptors bind chemokines (P=0.028), defensins (P=0.028) and metabolism of angiotensinogen (P=0.040). Conclusion: These findings suggest that the identified pathways may contribute to cancer progression and weaken the immune response in diffuse large B-cell lymphoma patients. This study offers fresh insights into previously undiscovered downstream targets and pathways modulated by diffuse large B-cell lymphoma. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of Araucaria sp. brown propolis (ABP) against trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. Methods: Animals received vehicle (1% DMSO, 1 ml/kg) or hydroalcoholic extract of ABP (hydroalcoholic extract of Araucaria sp. brown propolis (HEABP), 30, 100, and 300 mg/kg) orally, or dexamethasone (25 mg/kg, s.c.) for 5 days. On day 4, the animals received intracolonic TNBS (150 mg/kg), on day 6 they were euthanized. The weight of the animals, the macroscopic and microscopic colonic damage, reduced glutathione (GSH) and malondialdehyde (MDA) levels, and the activity of glutathione S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), and myeloperoxidase (MPO) were measured in colon homogenate. The action of HEABP and two isolated compounds in neutrophil migration was recorded. Key findings: HEABP (100 and 300 mg/kg), but not dexamethasone, decreased colonic lesion, and increased colonic mucin staining. In parallel, HEABP decreased MDA and restored GSH levels and the activity of SOD, CAT, and GST in the colon. A dose-dependent inhibition of MPO activity was observed (LogIC50 = 1.9). Moreover, HEBPA and the junicedric and abietic acids inhibited the neutrophil chemotaxis in vitro and HEBPA reduced neutrophil migration in vivo. Conclusion: HEABP may be promising in the therapies for inflammatory bowel diseases, reducing oxidative and inflammatory damage, especially mediated by neutrophils. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 can have long-lasting effects, but the effects on blood parameters and inflammation are poorly understood. The aim of this study was to evaluate morphological and inflammatory markers in long-term COVID-19 patients. Aim: To evaluate complete blood count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and morphology in mild versus severe long COVID-19. Material and methods: In total, 39 long COVID-19 patients were stratified into mild (n = 25) and severe (n = 14) groups. Blood counts, NLR, PLR were measured. Cell morphology was analysed. ROC curves were used to determine biomarker thresholds. Survival was assessed using Kaplan-Meier curves. Results and discussion: Severe patients had lower leukocytes but higher neutrophils, indicating greater inflammation. NLR and PLR were significantly increased in severe patients compared to mild patients (NLR 12 vs 8; PLR 140 vs 100). NLR and PLR were higher than in controls, confirming their utility as inflammatory markers. NLR and PLR effectively discriminated between mild and severe disease. High NLR and PLR predicted poorer prognosis. Altered leukocyte morphology such as cytoplasmic vacuolization correlated with severity. Conclusions: NLR and PLR are promising biomarkers for assessing severity of long COVID-19, while morphological changes in blood cells provide additional evidence of inflammation. Further studies in larger populations are warranted. [ABSTRACT FROM AUTHOR]

Aseptic pustulosis involves inflammatory skin conditions with nonbacterial pustules on erythema, accompanied by neutrophil and eosinophil infiltration in the epidermis. Dysregulation of the interleukin (IL)-36 pathway leads to neutrophil aggregation and pustule formation. Variants in IL36RN , CARD14 , AP1S3 , MPO , SERPINA3 and BTN3A3 have been identified in generalized pustular psoriasis (GPP) in the past. Some patients with acrodermatitis continua of Hallopeau (ACH), palmoplantar pustulosis and acute generalized exanthematous pustulosis (AGEP) also exhibit mutations in IL36RN , CARD14 and AP1S3 , albeit with regional and population-specific variations. This study aims to explore a shared genetic foundation among those with aseptic pustulosis. We performed Sanger sequencing on six genes in 126 patients with aseptic pustulosis. Genetic analysis identified IL36RN variants strongly associated with ACH, AGEP and subcorneal pustular dermatosis (SPD). Immunohistochemistry revealed elevated inflammatory cytokines in all subtypes. This study establishes a significant association between IL36RN variants and ACH, AGEP and SPD, emphasizing the IL-1/IL-36–chemokine–neutrophil axis as a common pathogenic mechanism. Targeting this axis holds promise for therapeutic interventions for aseptic pustulosis. [ABSTRACT FROM AUTHOR]

Neutrophils, the most abundant white blood cells in the human circulation, play crucial roles in various diseases, including kidney disease. Traditionally viewed as short-lived pro-inflammatory phagocytes that release reactive oxygen species, cytokines and neutrophil extracellular traps, recent studies have revealed their complexity and heterogeneity, thereby challenging this perception. Neutrophils are now recognized as transcriptionally active cells capable of proliferation and reverse migration, displaying phenotypic and functional heterogeneity. They respond to a wide range of signals and deploy various cargo to influence the activity of other cells in the circulation and in tissues. They can regulate the behavior of multiple immune cell types, exhibit innate immune memory, and contribute to both acute and chronic inflammatory responses while also promoting inflammation resolution in a context-dependent manner. Here, we explore the origin and heterogeneity of neutrophils, their functional diversity, and the cues that regulate their effector functions. We also examine their emerging role in infectious and non-infectious diseases with a particular emphasis on kidney disease. Understanding the complex behavior of neutrophils during tissue injury and inflammation may provide novel insights, thereby paving the way for potential therapeutic strategies to manage acute and chronic conditions. By deciphering their multifaceted role, targeted interventions can be developed to address the intricacies of neutrophil-mediated immune responses and improve disease outcomes. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) is an acute liver disease with a high mortality rate in clinical practice, characterized histologically by extensive hepatocellular necrosis and massive neutrophil infiltration. However, the role of these abnormally infiltrating neutrophils during ALF development is unclear. Here, in an ALF mouse model, metabolites were identified that promote the formation of neutrophil extracellular traps (NETs) in the liver, subsequently influencing macrophage differentiation and disease progression. ALF occurs with abnormalities in hepatic and intestinal metabolites. Abnormal metabolites (LTD4 and glutathione) can directly, or indirectly via reactive oxygen species, promote NET formation of infiltrating neutrophils, which subsequently regulate macrophages in a pro‐inflammatory M1‐like state, inducing an amplification of the destructive effects of inflammation. Together, this study provides new insights into the role of NETs in the pathogenesis of ALF. [ABSTRACT FROM AUTHOR]

Psoriasis is an inflammatory skin disease with various symptoms of differing severities and with the reported prominent involvement of neutrophil extracellular traps (NETs). The excitation of neutrophils, e.g., by interleukin 8 (IL-8) or lipopolysaccharide (LPS), leads to the citrullination of histones and the release of protein–DNA complexes into the extracellular space, where they are digested by DNases. Our aim was to explore data on the levels of protein-complexed DNAs neutrophil elastase–DNA (NE-DNA) and myeloperoxidase–DNA (MPO-DNA), citrullinated histones (citH2, citH3, citH4), and NET-degrading enzyme DNase I in the serum of psoriatic patients with varying severities of clinical symptoms assessed with the Psoriasis Area Severity Index (PASI), Body Surface Area (BSA), and Dermatology Life Quality Index (DLQI) scores. The levels of factors were detected in 52 patients with psoriasis and 22 healthy volunteers by the enzyme-linked immunosorbent assay (ELISA). The results showed the elevated levels of NE-DNA, MPO-DNA, citH3, and DNase I in the patients with psoriasis compared to healthy volunteers (p < 0.05). Additionally, changes were noticed in the levels of NE-DNA, citH3, and DNase I, depending on the severity of symptoms (p < 0.05). In mild psoriasis (PASI < 10, BSA < 10, DLQI < 10), the suppressing activity of the enzyme caused the impaired ability to remove the physiological level of NETs, whereas in moderate to severe psoriasis (PASI ≥ 10, BSA ≥ 10, DLQI ≥ 10), the enhanced activity of DNase I failed to remove NETs due to the observed overexpression. It may, thus, be concluded that the mechanism of action of NETs, which play an undeniable role in psoriatic diseases, seem to follow two different paths depending on the severity of disease, which may be crucial in selecting potential anti-NET treatment methods. [ABSTRACT FROM AUTHOR]

Neutrophil dysfunction is a form of immune suppression in patients with β-thalassemia (Beta-thal), although data on this are limited. In this study, blood from patients and healthy volunteers was analyzed. Flow cytometry analysis demonstrated an increase in immature neutrophils (CD16− CD62L+) and aged (senescent) neutrophils (CD16+ CD62L−) in Beta-thal patients compared to healthy volunteers. The Beta-thal neutrophils demonstrated less prominent chemotaxis and phagocytosis than healthy neutrophils at the baseline. With phorbol myristate acetate (PMA) or lipopolysaccharide (LPS) stimulations, some of the indicators, including the flow cytometry markers (CD11b, CD62L, CD66b, CD63, apoptosis, and reactive oxygen species) and neutrophil extracellular traps (NETs; detected by anti-citrullinated histone 3 immunofluorescence), were lower than the control. Additionally, low-density neutrophils (LDNs), which are found in the peripheral blood mononuclear cell (PBMC) fraction, were observed in Beta-thal patients but not in the control group. The expression of CD11b, CD66b, CD63, arginase I, and ROS in LDNs was higher than the regular normal-density neutrophils (NDNs). The proliferation rate of CD3+ T cells isolated from the PBMC fraction of healthy volunteers was higher than that of the cells from patients with Beta-thal. The incubation of red blood cell (RBC) lysate plus ferric ions with healthy NDNs transformed the NDNs into the aged neutrophils (decreased CD62L) and LDNs. In conclusion, iron overload induces neutrophil diversity along with some dysfunctions. [ABSTRACT FROM AUTHOR]

Non-melanoma skin cancers (NMSC), including basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and Merkel cell carcinoma (MCC), are increasingly common and present significant healthcare challenges. Neutrophil extracellular traps (NETs), chromatin fibers expulsed by neutrophil granulocytes, can promote immunotherapy resistance via an impairment of CD8+ T cell-mediated cytotoxicity. Here, to identify a potential therapeutic target, we investigate the expulsion of NETs and their relation to CD8+ T cell infiltration in NMSC. Immunofluorescence staining for neutrophils (CD15) and NETs (H3cit), as well as immunohistochemistry for cytotoxic T cells (CD8+) on human cSCCs (n = 24), BCCs (n = 17) and MCCs (n = 12), revealed a correlation between neutrophil infiltration and ulceration diameter in BCC and MCC, but not in cSCC. In BCC and cSCC, neutrophil infiltration also correlated with the cross-sectional area (CSA). NETs were not associated with established risk factors but with the presence of an ulceration, and, in cSCC, with abscess-like structures. CD8+ T cell infiltration was not reduced in tumors that were NET-positive nor in those with a denser neutrophil infiltration. This study is the first to report and characterize NETs in NMSC. Thus, it gives an incentive for further research in this relevant yet understudied topic. [ABSTRACT FROM AUTHOR]

Simple Summary: Daratumumab (DARA) plus bortezomib, thalidomide, and dexamethasone (D-VTd) represent the standard of induction care in Europe for autologous stem cell transplantation (auto-SCT)-eligible, newly diagnosed multiple myeloma (NDMM) patients. This study aimed to investigate the possible impact of D-VTd induction therapy on hematopoietic engraftment after auto-SCT. Our findings indicate that patients treated with D-VTd experienced longer neutrophil and platelet engraftment times than those treated with VTd. Additionally, D-VTd treatment was associated with a higher incidence of febrile neutropenia and grade 2 or higher diarrhea. However, no significant differences were observed in the median number of days to discharge. The conclusion we can draw from our real-life study is that a four-drug induction therapy containing DARA does not impact transplant safety outcomes. Background: This real-life study aimed to investigate the possible impact of D-VTd induction therapy on hematopoietic engraftment after autologous stem cell transplantation (auto-SCT). Methods: Sixty consecutive NDMM patients received four cycles of induction therapy with D-VTd. The conditioning regimen consisted of melphalan 200 mg/m2. These patients were compared with a historical control group of 80 patients who received four cycles of VTd as induction therapy. Results: The median days to reach neutrophil and platelet engraftment significantly differed between patients treated with D-VTd (11 and 13 days, respectively) and VTd (10 and 12 days). Univariate Cox analyses show that patients treated with D-VTd had a hazard ratio of neutrophil engraftment that was 42% significantly lower than those in the VTd arm (HR: 0.58, p = 0.002), and a multivariate model confirmed this result. Patients treated with D-VTd developed FN more frequently. Univariate and multivariate logistic regressions revealed an association between D-VTd and FN. Delayed engraftment did not correlate with more extended hospitalization. No patients died in the first six months after transplantation. Conclusions: Our real-life study showed that a four-drug induction therapy containing DARA does not impact transplant safety outcomes. [ABSTRACT FROM AUTHOR]

Among several quantitative trait loci involved in tuberculosis (TB) control in mice, one was mapped within the chromosome 17 segment occupied by the H2 complex and another within the chromosome 3 segment comprising the S100A8/9 genes, which encode neutrophil inflammatory factor S100A8/9. Previously, we developed a panel of H2‐congenic mouse strains differing by small segments of the major histocompatibility complex Class II (MHC‐II) region from TB‐susceptible H2j mice transferred onto the genetic background of the TB‐resistant C57BL/6 (H2b) strain. Susceptible B6.I‐9.3 mice differ from B6 progenitors by the alleles of their only classical MHC‐II H2‐Aβ gene. The goals of the present study were to: (i) comprehensively characterise the differences in TB‐related phenotypes between mice of the two strains and (ii) decipher interactions between the H2‐Aβ and S100A8/9 genes. Here, we describe the dynamics of TB‐related phenotypes differentiating B6.I‐9.3 and B6 mice (colony forming units counts, histopathology, lung immune cell infiltration and cytokine profiles). We show that disproportionally diminished CD4+ T‐cell population, an enlarged S100A8/9‐positive neutrophil population and higher S100A8/9 serum levels in B6.I‐9.3 mice collectively form the 'susceptible' phenotype before infection. An increase in IL‐17 and a decrease in intrferon‐gamma production by CD4+ T‐cells in these mice provide a mechanistic explanation of this phenotype. Using F2 segregation analysis, we show that the number of S100A8/9‐producing neutrophils in lungs and spleens and the proportion of Th17 CD4+ T‐cells in lungs are significantly lower in the presence of the MHC‐II dominant 'resistant' b allele compared to the recessive 'susceptible' j/j genotype. This provides direct genetic evidence that MHC‐II‐regulated CD4+ T‐cell landscapes determine neutrophil abundance before infection, an important pathogenic factor in TB immunity. [ABSTRACT FROM AUTHOR]