Group A Streptococcus (GAS; Streptococcus pyogenes) is an important bacterial pathogen causing over 700 million superficial infections and around 500.000 deaths due to invasive disease or severe post-infection sequelae yearly. In spite of this major impact on society, there is currently no vaccine available against this bacterium. GAS strains can be separated into >250 distinct emm (M)-types, and protective immunity against GAS is believed to in part be dependent on type-specific antibodies. Here, we analyse the nature of protective immunity generated against GAS in a model of intraperitoneal immunization in mice. We demonstrate that multiple immunizations are required for the ability to survive a subsequent lethal challenge, and although significant levels of GAS-specific antibodies are produced, these are redundant for protection. Instead, our data show that the immunization-dependent protection in this model is induced in the absence of B and T cells and is accompanied by the induction of an altered acute cytokine profile upon subsequent infection, noticeable e.g. by the absence of classical pro-inflammatory cytokines and increased IFN-γ production. Further, the ability of immunized mice to survive a lethal infection is dependent on macrophages and the macrophage-activating cytokine IFN-γ. To our knowledge these findings are the first to suggest that GAS may have the ability to induce forms of trained innate immunity. Taken together, the current study proposes a novel role for the innate immune system in response to GAS infections that potentially could be leveraged for future development of effective vaccines.

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants raise concerns about decreased vaccine efficacy, vaccines continue to confer robust protection in humans, implying that immunity beyond neutralization contributes to vaccine efficacy. In addition to neutralization, antibodies can mediate various Fc-dependent effector functions, including antibody-dependent cellular phagocytosis (ADCP), antibody-dependent neutrophil phagocytosis (ADNP) and antibody-dependent cellular cytotoxicity (ADCC). However, the specific role of each Fc-mediated effector function in contributing to COVID-19 disease attenuation in human remains unclear. To fully define the potential immune correlates of Fc-mediated effector functions, we comprehensively analysed the above Fc-mediated effector functions in two study cohorts. In the CoronaVac vaccinee cohort, individuals without breakthrough infection exhibited higher levels of ADCP and ADNP activities with a greater degree of cross-reactivity compared to those who had breakthrough infection. A predictive model was established incorporating ADNP activity and IgG titre, achieving an area under the curve (AUC) of 0.837. In the COVID-19 patient cohort, BA.5-specific ADCP and ADNP responses were significantly reduced in COVID-19 patients with fatal outcomes compared to milder outcomes. The prognostic model incorporating WT, BA.5, and XBB.1.5 spike-specific ADNP demonstrated effective predictive ability, achieving an AUC of 0.890. Meanwhile, transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients in the acute phases of infection highlighted remarkably upregulation of neutrophil activity and phagocytic function, further reinforcing the essential role of ADNP. Collectively, our findings underscored Fc-mediated effector activities, especially neutrophil phagocytosis, as significant antibody biomarkers for the risk of SARS-CoV-2 breakthrough infection and COVID-19 prognosis.

Emerging evidence suggests that immune dysregulation plays a pivotal role in triggering cryptogenic new-onset refractory status epilepticus (c-NORSE), prompting a consensus on early initiation of immunotherapy. However, despite similar timing of administration, responses to immunotherapies have been varied and unpredictable, suggesting the presence of heterogeneous underlying mechanisms. The aim of this study was to identify distinct inflammatory response subtypes in patients with c-NORSE by analyzing their cytokine profiles. Insights into underlying mechanisms were sought to understand the pathophysiology and guide personalized therapies to improve patient outcomes.

Sixty-two patients with c-NORSE were included. A comprehensive panel of 96 cytokines was analyzed in serum samples. Patients were clustered based on their cytokine profiles using the Louvain algorithm, an unsupervised graph-based clustering method. The identified clusters of patients were compared regarding cytokine levels and clinical features. Protein pathway analysis was used to explore the biological relevance of the inflammatory markers within each cluster. Patients with c-NORSE were compared with control patients (n = 18) and patients with other forms of refractory SE (n = 45).

Compared with controls, patients with c-NORSE exhibited significant differences in 33 cytokines. Pathway analysis revealed dysregulations in chemotaxis and neutrophil recruitment and migration, highlighting the importance of innate immunity in patients with c-NORSE. Within the c-NORSE cohort, 3 clusters of patients emerged: cluster A, lacking specific inflammatory markers; cluster B, with a much stronger innate-immunity cytokine-driven inflammatory response compared with clusters A and C; and cluster C, defined by dysregulated autoimmune processes. Notably, patients in cluster B showed a statistically significant elevation of innate immune-related proinflammatory cytokines associated with leukocyte recruitment and degranulation. By contrast, those in cluster C showed activation of Janus kinase signal transducer and activator of transcription (JAK-STAT) pathways, suggesting autoimmune mechanisms. Patients in clusters B and C demonstrated varied responses to immunotherapies, with cluster C patients showing favorable outcomes after multiple immunotherapies.

The identification of distinct inflammatory subgroups in c-NORSE suggests that variations in the underlying immune mechanisms contribute to differential treatment responses. These findings underscore the importance of personalized therapeutic strategies, potentially targeting specific inflammatory pathways, to optimize clinical outcomes in this challenging condition.

The Coronin family, a class of actin-binding proteins involved in the formation and maintenance of cytoskeleton structural stability, is aberrantly expressed in various tumors, including lung, gastric and head and neck cancers. They can regulate tumor cell metabolism and proliferation through RAC-1 and Wnt/β-Catenin signaling pathways and regulate invasion by influencing the PI3K, PAK4, and MT1-MMP signaling pathways and impacting the actin-network dynamics. In recent years, an increasing number of studies have highlighted the crucial roles of the cytoskeleton and immune modulation in the occurrence and development of tumors. The article delves into the Coronin family's pivotal role in tumor immune evasion, highlighting its modulation of neutrophil, T cell, and vesicular transport functions, as well as its interactions with tumorigenesis related organelles such as the endoplasmic reticulum, Golgi apparatus, mitochondria, and lysosomes. It also summarizes the potential therapeutic applications of the Coronin family in oncology. This review provides valuable insights into the mechanisms through which the Coronin family is implicated in the onset and progression of tumors. It also provides more theoretical foundation for tumor immunotherapy and combination drug therapy.

Neutrophil transdifferentiation involves the acquisition of dendritic cell-like properties, challenging the traditional view of neutrophils being solely phagocytes. The presence of transdifferentiated neutrophils is established in Visceral Leishmaniasis, but not in its dermal sequel, Post Kala-azar Dermal Leishmaniasis. Accordingly, this study investigated the altered functionalities of neutrophils focusing on the acquisition of dendritic cell-like properties and its impact on infection establishment. In PKDL cases, immunophenotyping of neutrophil-dendritic cells (N-DC hybrids) was performed using flow cytometry, along with studying the status of N-DC hybrid inducing cytokines (TNF-α, IFN-γ) and growth factor (GM-CSF). Ex vivo infection of neutrophils with L. donovani was monitored by droplet digital PCR, employing A2; additionally, their frequency of transdifferentiation, oxidative and phagocytic status, as well as apoptosis potential were quantified by flow cytometry. Compared with healthy controls, neutrophils from PKDL cases demonstrated a significant upregulation of CD83 positivity, but the frequency of co-stimulation (HLA-DR, CD80/86) was unaltered. PKDL cases demonstrated raised levels of TNF-α and IFN-γ, but GM-CSF remained unchanged. Following ex vivo infection of neutrophils, infection was evident at 2 h and was accompanied by CD83 positivity. Furthermore, the CD66b+/CD83 vis-à-vis CD66b+/CD83- subset exhibited heightened generation of reactive oxygen species (ROS), enhanced phagocytosis, and increased apoptosis. Taken together, neutrophils from PKDL cases demonstrated transdifferentiation with the absence of antigen-presenting function. Virulent Leishmania induced transdifferentiation in neutrophils, altering their functionalities and facilitating parasite uptake, along with heightened generation of intra-neutrophilic ROS and enhanced apoptosis, which possibly facilitated their engulfment by macrophages, thereby bolstering the "Trojan horse" mechanism of parasite transfer.

Human neutrophils express numerous G protein-coupled receptors (GPCRs) of importance for immune regulation. However, several functionally characterized neutrophil GPCRs, are not included within the human neutrophil proteome. To identify GPCRs not previously demonstrated to be expressed in human neutrophils, we utilized a microfluidic flow cell technique in conjunction with subcellular granule fractionation and liquid chromatography-tandem mass spectrometry (LC-MS/MS). This approach led to the identification of hydroxy-carboxylic acid 3 receptor (HCA3R, also known as GPR109B) as a novel component of the human neutrophil proteome. The β-oxidation intermediate 3-hydroxy-octanoic acid (3-OH-C8) is the primary endogenous agonist of the HCA3R and expressed at high levels in adipocytes where it exerts anti-lipolytic effects. However, literature describing the role and function of HCA3R in human neutrophils is scarce. We show that 3-OH-C8, as well as the synthetic HCA3R agonist IBC 293, activate human neutrophils determined as an increase in the intracellular concentration of free calcium ions ([Ca2+]i) and activation of the NADPH oxidase. However, in contrast to the rise in [Ca2+]i, which could be triggered in naïve neutrophils, pre-treatment of neutrophils was required for the HCA3R agonists to activate the NADPH oxidase. That is, the HCA3R-mediated NADPH oxidase activation occurred only in neutrophils pre-treated with either an actin cytoskeleton disrupter or an allosteric modulator targeting the GPCR termed free fatty acid receptor 2 (FFA2R). Our findings demonstrate that HCA3R is not only a new member of the human neutrophil proteome but also exhibits functional activity with complex signaling pathways when stimulated with endogenous and synthetic HCA3R agonists.

Enterovirus A71 (EV-A71) is the major causative pathogen for severe hand-foot-mouth disease (HFMD), a predominantly childhood-associated communicable disease. The mechanisms that children manifest severe disease progression while adults typically exhibit milder or asymptomatic infections remain incompletely characterized, which hinders the development of effective therapy against this disease. Herein, using the newborn mouse model of EV-A71 infection, we uncovered that the underdevelopment of T cells closely associated with the severity of EV-A71 infection, and EV-A71 infection dramatically impaired T-cell immune response. Moreover, the dysfunction of T-cell immunity contributes to the pathogenesis of EV-A71 infection, as the loss of T cells made neonatal mice highly vulnerable to EV-A71 infection. To further assess the relationship between T-cell immunity and HFMD, we enrolled a cohort of 145 pediatric patients with laboratory-confirmed EV-A71 infection and found that the compromised T-cell immune response is associated with the severity of EV-A71-caused HFMD in these children. Furthermore, we found that the treatment of newborn mice with Astragaloside A, a saponin from the medicinal herb Astragalus membranaceus, showed potent in vivo therapeutic efficacy against EV-A71 infection in a T-cell-dependent manner. In conclusion, these findings uncover the interaction between EV-A71 infection and T-cell immunity, provide novel insights onto the physiological impacts of T cells on the pathogenesis of EV-A71 infection and HFMD, and find a promising immunotherapeutic strategy to treat this viral disease.

This study aimed to investigate the role of immunotrophic inflammatory markers in assessing the prognosis and treatment-related toxicity in patients with esophageal squamous cell carcinoma (ESCC) undergoing first-line radiotherapy and chemotherapy combined with immunotherapy. We retrospectively enrolled 67 patients with ESCC and determined the optimal cutoff values for prognostic nutrition index (PNI), neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR) using receiver operating characteristic (ROC) curve analysis. Statistical analysis was performed using SPSS 25.0. The one-, two-, and three-year overall survival (OS) rates were 88.1%, 62.3%, and 57.6%, respectively. The overall effective rate was 82.1% (55/67). ROC curve analysis revealed optimal cutoff values for PNI, NLR, and PLR as 48.35, 3.84, and 150.49, respectively. Patients in the high PNI group, low NLR group and PLR group exhibited significantly higher mOS and mPFS time compared to the control group. Notably, the incidence of grade 2 toxicity and side effects in the PNI ≥ 48.35 group was significantly lower than that in the PNI < 48.35 group. Our findings suggest that pretreatment values of PNI, NLR, and PLR can serve as valuable biomarkers for evaluating the prognosis of ESCC patients undergoing first-line radiotherapy and chemotherapy combined with immunotherapy. Further studies with larger cohorts are warranted to validate these results.

Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, is characterized by chronic intestinal inflammation and immune dysregulation, driven mainly by Th1 and Th17 cells and sustained by pro-inflammatory cyto-chemokines. This inflammatory milieu is associated with visceral pain, a key symptom affecting patient quality of life. Addressing both gut inflammation/immunity and visceral pain is crucial for improving IBD therapy. This study assessed the therapeutic potential of Mangifera indica L. extract (MIE), a mangiferin-rich formulation, in a DNBS-induced colitis model in rats. MIE treatment administered either simultaneously or post-DNBS induction, significantly reduced pathogenic Th1 and Th17 cell infiltration, along with pro-inflammatory cytokines (IL-1β, TNF-α) and chemokines (CXCL1, CXCL2), though histopathology showed no significant improvements in tissue healing. Additionally, MIE restored microbiota-derived short-chain fatty acids (acetate and butyrate) in colon and faecal samples. Importantly, MIE alleviated post-inflammatory visceral hypersensitivity, reducing the abdominal withdrawal reflex (AWR) to colorectal distension (CRD), after either acute or repeated treatment. These findings suggest that MIE, in the context of nutraceuticals and functional foods, shows promise as a dual-action therapeutic strategy for complementary and/or adjuvant therapy in IBD.

Ovarian cancer (OC) remains the leading cause of cancer-related deaths among women, often diagnosed at advanced stages due to the lack of effective early diagnostic procedures. To reduce the high mortality rates in OC, reliable biomarkers are urgently needed, especially to detect OC at its earliest stage, predict specific drug responses, and monitor patients. The cytokine interleukin-6 (IL6) is associated with low survival rates, treatment resistance, and recurrence. In this review, we summarize the role of IL6 in inflammation and how IL6 contributes to ovarian tumorigenesis within the tumor microenvironment, influencing whether the tumor is subsequently classified as "hot" or "cold". We further dissect the molecular and cellular mechanisms through which IL6 production and downstream signaling are regulated, to enhance our understanding of its involvement in OC development, as well as OC resistance to treatment. We highlight the potential of IL6 to be used as a reliable diagnostic biomarker to help detect OC at its earliest stage, and as a part of predictive and prognostic signatures to improve OC management. We further discuss ways to leverage artificial intelligence and machine learning to integrate IL6 into diverse biomarker-based strategies.

Immune checkpoint inhibitors (ICIs) are shown to improve cancer treatment effectiveness by boosting the immune system of the patient. Nevertheless, the unique and highly suppressive TME poses a significant challenge, causing heterogeneity of response or resistance in a considerable number of patients. This review focuses on the evasive attributes of the TME. Immune evasion mechanism in TME include immunosuppressive cells, cytokine and chemokine signaling, metabolic alterations and overexpression of immune checkpoint molecules such as PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA and their interactions within the TME. In addition, this review focuses on the overcoming resistance by targeting immunosuppressive cells, normalizing tumor blood vessels, blocking two or three checkpoints simultaneously, combining vaccines, oncolytic viruses and metabolic inhibitors with ICIs or other therapies. This review also focuses on the necessity of finding predictive markers for the stratification of patients and to check response of ICIs treatment. It remains to be made certain by new research and intelligent innovations how these discoveries of the TME and its interplay facilitate ICI treatment and change the face of cancer treatment.

The patterns of postoperative recurrence vary among hepatocellular carcinoma (HCC) patients and infiltration of immune cells is correlated with patients prognosis. The present study aimed to develop and assess novel nomogram models for postsurgical recurrence and survival in HCC patients by combination of immune cell scores and clinicopathological features.

A total of 233 patients with curative hepatic resection and complete clinicopathologic information were enrolled. The infiltration of CD8 + T lymphocytes, CD15 + neutrophils and CD68 + macrophages in the tumor microenvironment was assessed by immunohistochemistry in tissue microarray. Two prognostic nomogram models for disease-free survival (DFS) and overall survival (OS) were developed and multi-dimensionally evaluated to predict postsurgical HCC outcomes.

The DFS nomogram was developed using AFP, GGT, tumor differentiation, Ki-67, and the densities of intratumoral CD15 + neutrophils and CD68 + macrophages. The OS nomogram was established based on gender, AFP, tumor differentiation, number of tumor nodules, microvascular vascular tumor thrombus (MVTT), Ki-67, microvessel density (MVD), the densities of intratumoral CD15 + neutrophils and CD68 + macrophages. The C-indexes for the DFS and OS nomogram were 0.708 (95% CI, 0.675-0.741) and 0.723 (95% CI, 0.688 to 0.758), respectively. The AUC values of the models for 1-, 2- or 5-year DFS were 0.832, 0.807 and 0.783, and for 1-, 2- or 5-year OS were 0.745, 0.794 and 0.842.

The present study proposed two nomogram models integrating infiltrating immune cells with clinicopathological risks and showed relatively good predictive performance of recurrence and survival, which may be beneficial to the clinical practice of HCC stratification. Further multicenter studies are needed to assess its general applicability.

FXII (coagulation factor XII) is best known for its roles in the contact and kallikrein-kinin pathways. FXII is converted to its active enzyme (FXIIa [activated factor XII]) by PKa (plasma kallikrein) or its unique ability to autoactivate on bacterial or other biologic surfaces. In vivo, FXIIa initiates the intrinsic coagulation pathway and promotes inflammation by reciprocal activation of prekallikrein, which cleaves HK (high-molecular-weight kininogen) to liberate bradykinin. CpaA (coagulation targeting metallo-endopeptidase of A baumannii) is a secreted metalloprotease identified in a human clinical isolate of Acinetobacter baumannii that cleaves FXII at O-linked glycosylated sites, inhibiting contact activation. While CpaA facilitates a modest in vivo fitness advantage in mice, the role of CpaA in human infection remains unclear. As such, the objectives of this study were to characterize the structural details of the interaction between CpaA, FXII, and the KKSs (kallikrein-kinin systems) and to determine the downstream consequences on thromboinflammatory responses.

The effect of purified CpaA on the coagulant activity of FXII and the generation of bradykinin was characterized. Neutrophil signaling, flow cytometry, and functional assays were performed to define how CpaA-mediated cleavage of FXII affects innate immune functions. Bacterial killing by human neutrophils was performed with wild-type and mutant A baumannii strains lacking CpaA.

We found that CpaA cleaves both FXII zymogen and FXIIa but not beta Factor XII. However, cleavage of FXIIa by CpaA does not significantly inhibit its clotting activity, demonstrating that CpaA does not inactivate FXIIa, but rather prevents activation of zymogen FXII. CpaA also cleaves HK, resulting in reduced kallikrein activation and bradykinin generation. We previously identified that zymogen FXII interacts with the urokinase receptor on neutrophils and upregulates neutrophil activation. Here, we demonstrate that CpaA cleaves neutrophil FXII, resulting in reduced Akt2 phosphorylation, chemotaxis, oxidative burst, and neutrophil extracellular trap formation. Importantly, CpaA decreases the human neutrophil killing efficiency of A baumannii in culture.

These data identify a role for FXII in responding to bacterial infection and suggest that by inhibiting the contact and KKSs and impairing neutrophil activation, CpaA may blunt the innate immune response and help prevent the elimination of A baumannii from the human host.

Microwave thermochemotherapy (MTC) has been applied to treat lip squamous cell carcinoma (LSCC), but a deeper understanding of its therapeutic mechanisms and molecular biology is needed. To address this, we used single-cell transcriptomics (scRNA-seq) and spatial transcriptomics (ST) to highlight the pivotal role of tumor-associated neutrophils (TANs) among tumor-infiltrating immune cells and their therapeutic response to MTC. MNDA+ TANs with anti-tumor activity (N1-phenotype) are found to be abundantly infiltrated by MTC with benefit of increased blood perfusion, and these TANs are characterized by enhanced cytotoxicity, ameliorated hypoxia, and upregulated IL1B, activating T&NK cells and fibroblasts via IL1B-IL1R. In this highly anti-tumor immunogenic and hypoxia-reversed microenvironment under MTC, fibroblasts accumulated in the tumor front (TF) can recruit N1-TANs via CXCL2-CXCR2 and clear N2-TANs (pro-tumor phenotype) via CXCL12-CXCR4, which results in the aggregation of N1-TANs and extracellular matrix (ECM) deposition. In addition, we construct an N1-TANs marker, MX2, which positively correlates with better prognosis in LSCC patients, and employ deep learning techniques to predict expression of MX2 from hematoxylin-eosin (H&E)-stained images so as to conveniently guide decision making in clinical practice. Collectively, our findings demonstrate that the N1-TANs/fibroblasts defense wall formed in response to MTC effectively combat LSCC.

Previous studies have suggested that trauma may be a risk factor for the development and prognosis of acral melanoma (AM).

This population-based retrospective cohort study included patients with AM and a confirmed history of trauma who received treatment at 5 melanoma treatment centers in China. Factors associated with recurrence and survival were analyzed using univariate and multivariate Cox regression analyses.

Totally 468 AM cases were included in this study, with 101 patients in the trauma group and 367 in the non-trauma group. The trauma group had more patients with ulceration (P = .027), mitotic rate ≥ 1 (P = .036), and Clark level IV-V (P = .009) than the non-trauma group. Among stage I-II postoperative AM patients, the median recurrence-free survival (RFS) was 33.3 months (95% CI: 18.8-47.8) and 115.6 months (95% CI: 96.3-135.0) in the trauma and non-trauma groups, respectively (P < .001). Similarly, the median overall survival (OS) was 64.6 (95% CI: 54.8-74.4) and not reached (95% CI: NR), respectively (P = .002). Comparatively, no significant differences were observed in RFS or OS between the trauma and non-trauma groups in patients with stage III and IV AM. Multifactorial analysis showed that trauma was an independent risk factor for RFS and OS only in patients with stage I-II AM patients.

Postoperative stage I-II patients in the trauma group had significantly worse RFS and OS compared to those in the non-trauma group.

Cervical squamous cell carcinoma (CESC) constitutes a substantial global health burden, especially in resource-limited regions. The identification of reliable biomarkers is critical for developing a clinically applicable nomogram to predict survival outcomes and evaluate immune infiltration in CESC patients.

This study integrated RNA-seq data from GEO and TCGA databases to identify key genes associated with CESC through differential expression analysis and machine learning techniques. Prognostic models were constructed and validated, with additional analyses exploring immune cell infiltration and gene function via GSEA and clinical correlation. Finally, key genes were validated via qRT-PCR in CESC tissues.

A total of 112 differentially expressed genes (DEGs) were identified through differential analysis of the GEO and TCGA datasets. EFNA1, CXCL8, and PPP1R14A emerged as prognostic biomarkers for CESC, showing significant associations with survival, tumor stage, and immune infiltration. EFNA1 may drive tumor progression via the MAPK signaling pathway, CXCL8 could influence immune evasion through NOD-like receptor signaling, and PPP1R14A may contribute to tumor invasion by modulating extracellular matrix remodeling. A nomogram integrating these genes demonstrated high predictive accuracy for overall survival (AUC>0.75) and calibration plots. Decision curve analysis (DCA) was performed to assess the nomogram's clinical utility and net benefit for application in clinical practice. Additionally, it was validated by qRT-PCR, showing elevated expression in tumors versus normal tissues (P<0.05).

EFNA1, CXCL8, and PPP1R14A are promising biomarkers for CESC prognosis and immune regulation. The nomogram model provides a practical tool for personalized survival prediction, enhancing clinical decision-making for immunotherapy and risk stratification.

The chemokine CXCL6 is identified as a pivotal regulator of biological processes across multiple malignancies. However, its function in cholangiocarcinoma (CCA) is underexplored. Tumor profiling for CXCL6 is performed using a public database. Both in vitro and in vivo experiments are utilized to evaluate the oncogenic effects of CXCL6 on CCA. Additionally, RNA-Seq is employed to detect transcriptomic changes related to CXCL6 expression in CCA cells and neutrophils. Molecular docking, fluorescence colocalization, and Co-IP are used to elucidate a direct interaction between JAKs and CXCR1/2. Additionally, LC-MS lipidomics and explored the impact of CXCL6 on immunotherapy in vivo. CXCL6 is upregulated in CCA tissues and promoted the proliferation and metastasis of CCA. Mechanistically, CXCL6 regulated the CXCR1/2-JAK-STAT/PI3K axis in CCA via autocrine signaling, leading to lipid metabolic reprogramming, and promoted neutrophil extracellular traps (NETs) formation by activating the RAS/MAPK pathway in neutrophils. Eventually, NETs formation induced immunotherapy resistance in CCA by blocking CD8+T cell infiltration. CXCL6 modulates CCA progression through the CXCR1/2-JAK-STAT/PI3K axis and reshaping its lipid metabolism. CXCL6 also mediates immunotherapy resistance through NETs, which may be a potential therapeutic target and biomarker for CCA.

Sepsis is characterized by a dysregulated host response to infection, leading to organ dysfunction and associated with significant morbidity and mortality, posing a critical challenge to global public health. Among its complications, sepsis frequently causes acute respiratory distress syndrome (ARDS), which has a high incidence and mortality rate, particularly in intensive care units (ICUs). Currently, the management of sepsis-induced ARDS is largely limited to supportive care, as no specific pharmacological treatments are available. The progression of sepsis to ARDS is driven by severe inflammation and cytokine storms, highlighting the importance of anti-inflammatory therapies as a primary treatment focus. We summarize conventional drugs and emerging treatments targeting excessive inflammatory responses in sepsis-associated ARDS, reviewing progress in basic research and clinical trials. Additionally, we discuss current research challenges to propose future directions for anti-inflammatory treatments, aiming to develop highly effective drugs with better clinical translation potential.

Periodontitis is a microbiome-related inflammation that can lead to irreversible bone reduction and even tooth loss. This study reveals that macrophage polarization states significantly influence periodontal homeostasis, with M2 macrophage-derived extracellular vesicles (M2-EVs) playing a pivotal role in mitigating periodontitis-induced bone loss. Single-cell RNA sequencing of periodontal tissues treated with M2-EVs uncovered a unique Anxa1hi neutrophil subpopulation exhibiting pro-reparative properties. This subpopulation is characterized by immaturity and demonstrated osteogenic and angiogenic capabilities in vivo, partially mediated through the secretion of oncostatin M (OSM) signals. The findings suggest that this functional heterogeneity arises from M2-EVs disrupting the neutrophil maturation trajectory, with pivotal reprogramming genes, such as Acvrl1 and Fpr2, driving the differentiation of the Anxa1hi reparative subpopulation. This work underscores the potential of targeting M2 macrophage-neutrophil interactions to promote the regeneration of inflamed bone tissues.

Polymorphonuclear leukocytes (PMNs) are terminally differentiated phagocytes with pivotal roles in infection, inflammation, tissue injury, and resolution. PMNs display a breadth of responses to diverse endogenous and exogenous stimuli, making understanding of these innate immune responders vital yet challenging to achieve. Here, we report a 22-color spectral flow cytometry panel to profile primary human PMNs for surface marker expression of activation, degranulation, phagocytosis, migration, chemotaxis, and interaction with fluorescently labeled cargo. We demonstrate the surface marker response of PMNs to phorbol ester stimulation compared with untreated controls in an adherent PMN model with additional analysis of intra- and inter-subject variability. PMNs challenged with the Gram-negative bacterial pathogen Neisseria gonorrhoeae revealed infectious dose-dependent changes in surface marker expression in bulk, population-level analysis. Imaging flow cytometry complemented spectral cytometry, demonstrating that fluorescence signal from labeled bacteria corresponded with bacterial burden on a per-cell basis. Spectral flow cytometry subsequently identified surface markers, which varied with direct PMN-bacterium association as well as those which varied in the presence of bacteria but without phagocytosis. This spectral panel protocol highlights best practices for efficient customization and is compatible with downstream approaches such as spectral cell sorting and single-cell RNA-sequencing for applicability to diverse research questions in the field of PMN biology.

Limited data exist on the clinical outcomes and inflammatory response of Enhanced Recovery After Surgery (ERAS) protocols in adolescent idiopathic scoliosis (AIS) patients undergoing posterior spinal fusion (PSF). This study evaluates ERAS's impact by analyzing blood parameters and serum protein, surgical, and radiological parameters to assess safety, feasibility, and clinical outcomes. Between July 2021 and July 2022, 30 AIS patients underwent PSF with standardized pain management, high-dose tranexamic acid, early mobilization, and reduced opioid use. Blood tests and serum markers (IL-6, IL-1β, IL-1α, IL-10, TNF-α, IL-8, PGE2) were measured preoperatively and on postoperative day 2. Pain levels (VAS) were recorded preoperatively, on postoperative days 1 and 2, and at discharge. Results showed increased postoperative white blood cell counts, reduced hemoglobin and hematocrit, and elevated C-reactive protein levels. IL-6 was the only inflammatory marker significantly elevated, indicating a controlled inflammatory response. Pain peaked on day 1 but significantly decreased by discharge, confirming the effectiveness of multimodal analgesia. The average hospital stay was 6.97 ± 2.03 days, with low rehospitalization (6.66%) and manageable complications (20%). In conclusion, ERAS effectively optimizes AIS patient recovery, stabilizing pain, reducing complications, and improving perioperative care.

Nucleic acid vaccines have grown in importance over the past several years, with the development of new approaches remaining a focus. We describe a lipid nanoparticle-formulated DNA (DNA-LNP) formulation which induces robust innate and adaptive immunity with similar serological potency to mRNA-LNPs and adjuvanted protein. Using an influenza hemagglutinin (HA)-encoding construct, we show that priming with our HA DNA-LNP demonstrated stimulator of interferon genes (STING)-dependent upregulation and activation of migratory dendritic cell (DC) subpopulations. HA DNA-LNP induced superior antigen-specific CD8+ T cell responses relative to mRNA-LNPs or adjuvanted protein, with memory responses persisting beyond one year. In rabbits immunized with HA DNA-LNP, we observed immune responses comparable or superior to mRNA-LNPs at the same dose. In an additional model, a SARS-CoV-2 spike-encoding DNA-LNP elicited protective efficacy comparable to spike mRNA-LNPs. Our study identifies a platform-specific priming mechanism for DNA-LNPs divergent from mRNA-LNPs or adjuvanted protein, suggesting avenues for this approach in prophylactic and therapeutic vaccine development.

Biomaterial coatings and films can prevent premature failure and enhance the performance of chronically implanted medical devices. However, current hydrophilic polymer coatings and films have significant drawbacks, including swelling and delamination. To address these issues, hydroxyethyl cellulose is modified with thioether groups to generate an oxidation-responsive polymer, HECMTP. HECMTP readily dissolves in green solvents and can be fabricated as coatings or films with tunable thicknesses. HECMTP coatings effectively scavenge hydrogen peroxide, resulting in the conversion of thioether groups to sulfoxide groups on the polymer chain. Oxidation-driven, hydrophobic-to-hydrophilic transitions that are isolated to the surface of HECMTP coatings under physiologically relevant conditions increase wettability, decrease stiffness, and reduce protein adsorption to generate a non-fouling interface with minimal coating delamination or swelling. HECMTP can be used in diverse optical applications and permits oxidation-responsive, controlled drug release. HECMTP films are non-resorbable in vivo and evoke minimal foreign body responses. These results highlight the versatility of HECMTP and support its incorporation into chronically implanted medical devices.

Gastric cancer (GC) is linked to high morbidity and mortality rates. Approximately two-thirds of GC patients are diagnosed at an advanced or metastatic stage. Conventional treatments for GC, including surgery, radiotherapy, and chemotherapy, offer limited prognostic improvement. Recently, immunotherapy has gained attention for its promising therapeutic effects in various tumors. Immunotherapy functions by activating and regulating the patient's immune cells to target and eliminate tumor cells, thereby reducing the tumor burden in the body. Among immunotherapies, immune checkpoint inhibitors (ICIs) are the most advanced. ICIs disrupt the inhibitory protein-small molecule (PD-L1, CTLA4, VISTA, TIM-3 and LAG3) interactions produced by immune cells, reactivating these cells to recognize and attack tumor cells. However, adverse reactions and resistance to ICIs hinder their further clinical and experimental development. Therefore, a comprehensive understanding of the advancements in ICIs for GC is crucial. This article discusses the latest developments in clinical trials of ICIs for GC and examines combination therapies involving ICIs (targeted therapy, chemotherapy, radiotherapy), alongside ongoing clinical trials. Additionally, the review investigates the tumor immune microenvironment and its role in non-responsiveness to ICIs, highlighting the function of tumor immune cells in ICI efficacy. Finally, the article explores the prospects and limitations of new immunotherapy-related technologies, such as tumor vaccines, nanotechnologies, and emerging therapeutic strategies, aiming to advance research into personalized and optimized immunotherapy for patients with locally advanced gastric cancer.

Noncystic fibrosis bronchiectasis, hereafter referred to as bronchiectasis, is a chronic, progressive lung disease that can affect people of all ages. Patients with clinically significant bronchiectasis have chronic cough and sputum production, as well as recurrent respiratory infections, fatigue and impaired health-related quality of life. The pathophysiology of bronchiectasis has been described as a vicious vortex of chronic inflammation, recurring airway infection, impaired mucociliary clearance and progressive lung damage that promotes the development and progression of the disease. This review describes the pivotal role of neutrophil-driven inflammation in the pathogenesis and progression of bronchiectasis. Delayed neutrophil apoptosis and increased necrosis enhance dysregulated inflammation in bronchiectasis and failure to resolve this contributes to chronic, sustained inflammation. The excessive release of neutrophil serine proteases, such as neutrophil elastase, cathepsin G and proteinase 3, promotes a protease-antiprotease imbalance that correlates with increased inflammation in bronchiectasis and contributes to disease progression. While there are currently no licensed therapies to treat bronchiectasis, this review will explore the evolving evidence for neutrophilic inflammation as a novel treatment target with meaningful clinical benefits.

As the site of gas exchange, the lung is critical for organismal survival. It is also subject to continual environmental insults inflicted by pathogens, particles, and toxins. Sometimes, these insults result in structural damage and the initiation of an innate immune response. Operating in parallel, the immune response aims to eliminate the threat, while the repair process ensures continual physiological function of the lung. The inflammatory response and repair processes are thus inextricably linked in time and space but are often studied in isolation. Here, we review the interplay of innate immune cells and nonimmune cells during lung insult and repair. We highlight how cellular cross talk can fine-tune the circuitry of the immune response, how innate immune cells can facilitate or antagonize proper organ repair, and the prolonged changes to lung immunity and physiology that can result from acute immune responses and repair processes.

Cancer is the second leading cause of death among humans worldwide. Despite remarkable improvements in cancer therapies, drug resistance remains a significant challenge. The tumor microenvironment (TME) is intimately associated with therapeutic resistance. Tumor‑associated neutrophils (TANs) are a crucial component of the TME, which, along with other immune cells, play a role in tumorigenesis, development and metastasis. In the current review, the roles of TANs in the TME, as well as the mechanisms of neutrophil‑mediated resistance to cancer therapy, including immunotherapy, chemotherapy, radiotherapy and targeted therapy, were summarized. Furthermore, strategies for neutrophil therapy were discussed and TANs were explored as potential targets for cancer treatment. In conclusion, the need to explore the precise roles, recruitment pathways and mechanisms of action of TANs was highlighted for the purpose of developing therapies that precisely target TANs and reverse drug resistance.

Neutrophil-to-lymphocyte ratio (NLR) is a readily available parameter, associated with long-term outcomes in cardiovascular conditions. This study aims to analyze the predictors of NLR and its impact on prognosis and disease-specific outcomes following endovascular aneurysm repair (EVAR).

Single-center retrospective cohort study. Consecutive patients who underwent elective EVAR (2011-2023) were considered. Primary outcome is short-term major adverse events (MAE) and long-term mortality. Secondary outcomes were freedom-from EVAR failure, aortic reintervention, and NLR predictors. Multivariable logistic regression analyses were performed for binary outcomes. Survival outcomes were analyzed through Kaplan-Meier and Cox regression analyses.

Overall, 434 patients were included. A 2.4 NLR cutoff was a fair discriminator for long-term-mortality (area under the curve, 0.62), and groups were dichotomized according to this premise. Increasing age (adjusted odds ratio [aOR]: 1.06; 1.03-1.09, per 1-year increase) and a pulmonary comorbidity (aOR: 1.91; 1.24-2.96) associated to NLR ≥ 2.4. No significant association between comorbidity burden and NLR was observed. MAE occurred more often if NLR ≥ 2.4 (6.2 vs. 11.6% high-NLR, P = 0.049; NLR ≥ 2.4 aOR: 2.10; 1.01-4.36). At 8-years follow-up, survival estimates favored NLR < 2.4 (55.7% vs. 33.7% high-NLR, P < 0.001, NLR ≥ 2.4 adjusted hazard ratio [aHR]: 1.07; 1.05-1.98), without differences in freedom-from EVAR failure (70.6 vs. 68.2% high-NLR, P = 0.27, NLR ≥ 2.4 aHR: 1.26; 0.82-1.94). Conversely, NLR ≥ 2.4 associated with lower freedom from aortic reinterventions (80.0% vs. 70.2% high-NLR, P = 0.01, NLR ≥ 2.4 aHR: 1.80; 1.08-3.01).

NLR appears as a prognostic marker with reduced impact of comorbidity burden. Following EVAR, it independently predicts MAE and mortality. Over time, elevated NLR appears associated with increased aortic reinterventions, although rates and mode of failure seem similar across groups.

Early failure of a pancreatic allograft due to complete thrombosis has an incidence of approximately 10% and is the main cause of comorbidity in pancreas transplantation. Although several risk factors have been identified, the exact mechanisms leading to this serious complication are still unclear. In this review, we define the roles of the individual components involved during sterile immunothrombosis-namely endothelial cells, platelets, and innate immune cells. Further, we review the published evidence linking the main risk factors for pancreatic thrombosis to cellular activation and vascular modifications. We also explore the unique features of the pancreas itself: the vessel endothelium, specific vascularization, and relationship to other organs-notably the spleen and adipose tissue. Finally, we summarize the therapeutic possibilities for the prevention of pancreatic thrombosis depending on the different mechanisms such as anticoagulation, anti-inflammatory molecules, endothelium protectors, antagonism of damage-associated molecular patterns, and use of machine perfusion.

Chromoblastomycosis (CBM), a chronic subcutaneous infection caused by black fungi such as Fonsecaea monophora (F. monophora), is characterized by a low cure rate, high recurrence rate, and prolonged treatment duration. Neutrophils, one of the most important innate immune cells, play complex roles in the prevention of fungal infections. This study investigated the function of neutrophils in host defense against F. monophora using a neutrophil-depleted mouse model and in vitro co-culture conditions. Fungal burden, histopathological changes, and cytokine profiles were compared between neutrophil-depleted mice and isotype control mice. Our findings demonstrated that neutrophil depletion in mice led to impaired fungal clearance, prolonged inflammation in F. monophora infected footpad tissues, highlighting the critical role of neutrophils in controlling F. monophora infection. Histopathological analysis revealed extensive inflammatory cell infiltration, especially macrophages, accompanied by elevated levels of pro-inflammatory cytokines such as IL-1β, CCL3, IL-6, and TNF-α. Besides, we observed that neutrophils play a key role in inhibiting the morphological transition of F. monophora from conidia to hyphae and sclerotic-like cells. Notably, the F. monophora morphology was also associated with the formation of neutrophil extracellular traps (NETs) in in vitro experiment. These findings underscore the importance of neutrophil-mediate immune responses in early fungal clearance and their ability to influence F.monophora morphological transition. The study provides novel insights into the immune mechanisms underlying CBM and highlights the potential therapeutic implications of targeting neutrophil-mediated responses in CBM infections.

Jasminum humile is widely used in traditional medicines to treat hard lumps, mouth inflammation, ringworms, and other infections. Leaf decoction of the plant is known to be effective in treating various skin conditions. In addition, root juice is traditionally utilized as a remedy for ringworm infections. Studies have reported that J. humile contains various antioxidant metabolites with analgesic and anti-inflammatory properties. In this study, J. humile chloroform extract (JHC) was investigated for anti-inflammatory effects against carrageenan-induced paw oedema in rat models.

High-performance liquid chromatography was used to examine phenolic compounds present in JHC. The in-vivo anti-inflammatory activities were investigated using carrageenan-induced paw oedema rat models, while indomethacin was referred to as positive control. Therapeutic properties of JHC were examined by assessing paw volumes, motility score, and inflammatory proteins in serum. The anti-inflammatory nature of JHC was further investigated by biochemical and hematological profiles along with genetic expression of inflammatory and antioxidant genes through qRT-PCR analysis.

Indomethacin at 10 mg/kg and JHC at 100, 200, and 300 mg/kg doses decreased the concentration of C-reactive protein (CRP) while upregulating the concentration of albumin and myeloperoxidase (MPO). Moreover, JHC administration reduced the expression levels of inflammatory markers, cyclooxygenase-2 (COX2), and inducible nitric oxide synthase (iNOS) compared to the Carr-treated control. However, a significant rise was induced in nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1) levels after JHC treatment as compared to Carr-treated rats.

These results showed significant anti-inflammatory potential of J. humile by increasing the activity levels of enzymatic antioxidants and lowering inflammatory markers. These results confirm the beneficial use of natural plants in the development of new anti-inflammatory drugs.

Rheumatoid arthritis (RA) is a systemic autoimmune disease involving activation of the immune system and the infiltration of immune cells. As the first immune cells to reach the site of inflammation, neutrophils perform their biological functions by releasing many active substances and forming neutrophil extracellular traps (NETs). The overactivated neutrophils in patients with RA not only directly damage tissues but also, more importantly, interact with various other immune cells and broadly activate innate and adaptive immunity, leading to irreversible joint damage. However, owing to the pivotal role and complex influence of neutrophils in maintaining homoeostasis, the treatment of RA by targeting neutrophils is very difficult. Therefore, a comprehensive understanding of the interaction pathways between neutrophils and various other immune cells is crucial for the development of neutrophils as a new therapeutic target for RA. In this study, the important role of neutrophils in the pathogenesis of RA through their crosstalk with various other immune cells and nonimmune cells is highlighted. The potential of epigenetic modification of neutrophils for exploring the pathogenesis of RA and developing therapeutic approaches is also discussed. In addition, several models for studying cell‒cell interactions are summarized to support further studies of neutrophils in the context of RA.

Inflammatory bowel disease (IBD) is a chronic recurrent IBD, whose cause involves the interaction between genetic and environmental factors. Although there is a recognized link between immune response and IBD, the causal relationship between circulating immune cell counts and IBD remains controversial. This study aimed to elucidate the causal relationship between genetically predicted circulating immune cell counts and IBD. We conducted a bidirectional 2-sample Mendelian randomization (MR) study using aggregated statistics from genome-wide association studies. The causal relationship between 5 circulating leukocytes cells (monocytes, lymphocytes, eosinophils, basophils and neutrophils) counts and IBD, including ulcerative colitis (UC) and Crohn disease (CD) was analyzed. Horizontal pleiotropy test and heterogeneity test were used to ensure the stability of the results. Our findings indicated that monocytes, lymphocytes, eosinophils, and basophils count were not significantly associated with IBD, however, elevated circulating neutrophils count was significantly associated with higher risk of IBD [odds ratio (OR) = 1.0017; 95% confidence interval (CI) = 1.0004-1.003; P = .009] and UC [OR = 2.465; 95% CI = 1.236-4.916; P = .01]. In addition, we also found that IBD [OR: 12.07; 95% CI = 1.909-76.316; P = .008] and CD [OR = 1.014; 95% CI = 1.004-1.023; P = .005] were significantly associated with higher circulating neutrophils count in reverse MR. This MR study provides genetic evidence for the causal relationship between the genetically predicted increase in circulating neutrophils count and the risk of IBD (UC and CD). This finding stresses the need for further exploring physiological functions of neutrophils in order to develop effective strategies against IBD.

Background/Objectives: Septic shock remains a significant clinical challenge with consistently high mortality rates. Recent investigations have focused on the efficacy of CytoSorb® (CytoSorbents Corporation, Monmouth Junction, NJ, USA), an extracorporeal cytokine adsorber, and how it impacts outcomes in sepsis. The current meta-analysis reports on the impact of CytoSorb® on survival, specifically in septic shock patients. Methods: We conducted a comprehensive systematic search across the PubMed and COCHRANE databases for studies published up to 10 June 2024. The analysis prioritized randomized controlled trials and observational studies with control groups involving septic shock patients while excluding case reports and case series. Nine studies were finally included in our meta-analysis following the initial screening of 115 articles after excluding duplicates and irrelevant entries. Results: The meta-analysis was performed on 744 critically ill patients with septic shock from one RCT and eight observational studies. Of these, 449 patients received treatment with CytoSorb® in addition to standard care. Our data indicate that CytoSorb® use is associated with reduced in-hospital mortality, evidenced by an odds ratio (OR) of 0.64 [0.42; 0.97] and a p-value of 0.036. For 28-30-day mortality, the findings were more pronounced with an OR of 0.49 [0.28; 0.83] and a p-value of 0.003. The analysis of the longest observed mortality showed a trend for improved survival within the CytoSorb group; however, it did not reach statistical significance. Additionally, there was a significant improvement in hemodynamic stability as a secondary endpoint, as evidenced by notable reductions in vasopressor requirements in the hemoadsorption group. Conclusions: The current meta-analysis suggests that the use of CytoSorb® alongside standard of care management may be linked to improved short-term survival in patients with septic shock; however, these findings should be interpreted with caution in light of the heterogeneity and the modest quality of the studies included. Prospective studies are needed to better determine the impact of hemoadsorption on shock reversal and survival in these critically ill patients.