Severe dengue is characterized by vascular leakage triggered by a hyperinflammatory response, though the underlying mechanisms remain unclear. Our previous mouse model study highlighted the importance of small intestine in severe disease and identified key cytokines (IL-17A, TNF-α, and IL-6) involved. Here, we used a Fixed RNA Profiling assay to characterize key cytokine- and effector-producing cells, along with their receptor expression. Type 3 innate lymphoid cells (ILC3), Th17 cells, and γδ T cells emerged as pathologically relevant IL-17A/F-producing cells. These cells expressed IL-1β and IL-23 receptors, underscoring the significance of these signaling pathways. IL-1β was produced by M2-like macrophages, dendritic cells, and neutrophils, whereas M1-like macrophages, which differentiated post-infection, produced IL-23, TNF-α, and IL-6, acting as initiators and amplifiers of the cytokine storm. Newly differentiated neutrophils produced IL-1β and effector molecule matrix metalloprotease-8, suggesting a dual role in exacerbating the cytokine storm and directly mediating vascular leakage. Identified macrophages and neutrophils exhibited atypical characteristics. These findings provide new pathological insights into severe dengue and broader mechanism underlying cytokine storm-related diseases.

Pregnancy requires a careful immune balance between tolerance for the semi-allogenic fetus and protection against pathogens. Women with immune-mediated inflammatory diseases (IMIDs), where the interleukin (IL)-23/IL-17 axis plays an important role, often experience changes in disease severity during pregnancy. These changes and the association between disease flares and pregnancy complications, suggests a role for IL-17 and IL-23 in pregnancy.

We systemically searched PubMed, EMBASE, and Web of Science (March 2024), to assess the role of IL-17 and IL-23 in pregnancy-related in vitro assays, animal or human studies.

Eighty articles (8 in vitro, 11 animal and 61 human studies) were included. Seventy-one studies reported on IL-17 and 16 studies on IL-23. In vitro trophoblast proliferation, migration and invasion was increased in the presence of IL-17, but impaired with IL-23. IL-17 levels were increased in animal models for pregnancy complications. In humans, IL-17 levels seemed to be increased in pregnant women versus non-pregnant women. Additionally, elevated IL-17 levels were associated with pregnancy complications. Although similar trends were found for IL-23, data were limited.

We identified a large, but heterogenic, body of evidence for a significant role of IL-17 in all stages of pregnancy: while an excessive increase seemed to be associated with complications. The limited number of studies prevents firm conclusions on the role of IL-23. Future research is needed to find biomarkers for patients with IMIDs to predict the effect of possible disease flares on pregnancy, and the effect of therapeutic inhibition of IL-17 or IL-23.

Brucellosis is a zoonotic disease, with an important economic impact on the livestock industry and public health worldwide. Both Brucella abortus and Brucella melitensis can infect Mediterranean Buffalo (Bubalus bubalis), leading to infertility and abortion. In ruminants, the standard diagnostic approach involves two serological tests, the Rose Bengal Test and the Complement Fixation Test, applied in parallel, though their specificity requires improvement. Cytokines play a crucial role in coordinating immune responses through complex networks and can serve as biomarkers for various diseases. This study explored the potential use of cytokines as immunological biomarkers for Brucella infection in Mediterranean Buffalo. For this purpose, we included 18 healthy and 20 Brucella-infected buffaloes in our analysis. Heparinized blood samples were stimulated with the Brucella antigen, with PBS as nil control and PWM as lymphocyte viability control. After 16-24 h, plasma levels of IL-1α, IL-1β, IL-4, IL-6, IL-10, IL-17, IL-36Ra, MIP-1α, MIP-1β, MCP-1, CXCL8, IP-10, IFN-γ, TNF, and VEGF-A were measured using multiplex ELISA. Our results showed that infected animals released significantly higher levels of IFN-γ, IP-10, MCP-1 in response to Brucella antigen compared to healthy controls. Conversely, healthy animals released instead higher levels of IL-1α, IL-1β, IL-6 and IL-10 following antigen stimulation compared to infected animals. Finally, sequential canonical discriminant analyses were performed to generate predictive cytokine profiles for each group. The findings indicated that a combination of five cytokines (IFN-γ, IP-10, IL-1α, IL-1β, IL-6) can effectively distinguished infected from healthy buffaloes. Overall, this study suggests that incorporating these key immune cytokines could improve the diagnostic accuracy of brucellosis in Mediterranean Buffalo.

The aim of this study was to systematically review literature on immune responses in liver tissue pathology in diabetes, focusing on immune cell populations and related cytokines. A systematic search of relevant English full-text articles up to June 2024 from online databases, covering animal and human studies, was conducted using the PRISMA workflow. Thirteen studies met criteria. Immune cells in the liver, including monocytes/macrophages, neutrophils, and iNKT and T cells, were implicated in liver inflammation and fibrosis in diabetes. Pro-inflammatory cytokines, including interferon-ɣ, tumor necrosis factor-α, interleukin (IL)-15, IL-18, and IL-1β were upregulated in the liver, potentially contributing to liver inflammation and fibrosis progression. In contrast, the anti-inflammatory cytokine IL-4 was downregulated, possibly attributing to chronic inflammation in diabetes. Pathological immune responses via the TLR4/MyD88/NF-κB pathway and the IL-17/IL-23 axis were also linked to liver fibrosis in diabetes. In conclusion, this review highlights the putative pivotal role of immune cells in diabetes-related liver fibrosis progression through their regulation of cytokines and signaling pathways. Further research on diabetes and dysmetabolic liver pathology is needed to clarify immune cell localization in the liver and their interactions with resident cells promoting fibrosis. Targeting immune mechanisms may provide therapeutic strategies for managing liver fibrosis in diabetes.

This study aimed to investigate the evidence for presence of Th17 cells and their biomarkers, and to assess their impact on the immune-inflammatory response in periodontitis.

An electronic search was performed in MEDLINE (PubMed), SCOPUS, EBSCOhost, and Google Scholar databases from their earliest records to April 2023. Additionally, the reference lists of included articles and grey literature were hand-searched. Study selection and quality assessment of the included articles was performed using the Newcastle-Ottawa scale.

This systematic review included case-control, cross-sectional, and cohort studies published in English, specifically those evaluating the presence and influence of Th17 or its related biomarkers in the progression of periodontal disease. Of the 26,797 articles screened, 47 studies met the eligibility criteria and were included. The studies varied in design, molecular methods, and sample types.

This systematic review confirms the presence of Th17 cells and related biomarkers in periodontal tissues, highlighting their role in the immune-inflammatory response and pathogenesis of periodontitis. The review underscores the need for more comprehensive research to overcome current limitations and effectively translate these findings into clinical practice.

The aim of the study was to find associations between the levels of liver injury serum markers and the selected liver, peripheral leukocytes, and plasma immune characteristics in biliary atresia (BA) children. Twenty-five newly diagnosed BA children aged 4-30 weeks and 12 age-matched controls were included (for leukocytes characteristics) and 19 BA children and 11 controls (for liver studies). The frequencies of T helper 1 (Th1), Th2, Th17, Th17.1 cells as well as numbers of regulatory T (Treg), B cell subsets, and matrix metalloproteinase -2 and -9 (MMP-2 and MMP-9) expressing leukocytes in the whole blood were evaluated by flow cytometry. Plasma concentrations of tissue inhibitors of metalloproteinase (TIMP)-1, -2, MMP-9, interleukin-17A (IL-17A) and IL-6 were assessed by enzyme-linked immunosorbent assay (ELISA). The leukocyte and liver expression of the retinoic acid receptor-related orphan nuclear receptor gamma (RORγT), fork-head winged helix transcription factor P3 (FoxP3), transforming growth factor beta (TGF-β), interleukin-17A (IL-17A), IL-6, IL-1β, IL-21, interleukin 1 receptor antagonist (IL-1Ra), MMP-2, MMP-9, MMP-12 (liver only), TIMP-1, TIMP-2, T-box transcription factor expressed in T cells, also called TBX21 (T-bet), GATA-binding protein 3 (GATA3), and C-type lectin (CD161) mRNA were determined by real time RT-PCR (reverse-transcription polymerase chain reaction). The BA patients were characterized by increased frequencies of peripheral "suppressor" glycoprotein-A repetitions predominant protein (GARP)+latency-associated peptide (LAP)+Treg and activated Treg cells as well as MMP-2 and MMP-9 bearing lymphocytes, elevated plasma TIMP-1 levels, increased leukocyte expression of MMP-9, TIMP-1, TIMP-2, IL-6, and TGF-β, and decreased leukocyte expression of IL-21 and T-bet, increased liver expression of FoxP3, TIMP-1, and decreased liver expression of IL-1β and MMP-2. The following correlations were found between serum markers of liver injury and leukocyte and liver immune characteristics: (a) hemoglobin (Hb) levels correlated negatively with frequency of peripheral "suppressor" GARP+LAP+ Tregs; (b) aspartate aminotransferase (AST) levels correlated positively with frequency of the peripheral Th17.1 subset and expression of leukocyte FoxP3, (c) gamma glutamyltransferase (GGT) levels correlated positively with the peripheral memory B cells frequencies, the leukocyte IL-6 and TIMP-1 gene expression, (d) alanine aminotransferase (ALT) serum levels correlated positively with the naïve B cell frequency and liver TIMP-2 expression, (e) total bilirubin (Bil) levels correlated positively with the leukocyte MMP-9, the plasma IL-6 levels, and the liver TIMP-2 gene expression, (f) direct Bil levels positively correlated with the liver IL-6 and TIMP-2 expression, (g) international normalized ratio of prothrombin time (PT/INR) concentrations correlated positively with the peripheral Th17.1 subset frequency and the leukocyte MMP-9 but negatively with the liver FoxP3 expression. There were numerous strong positive correlations between the BA liver genes known to be involved in upregulation of IL-17 axis and MMPs/TIMPs expression. No prevailing leukocyte or liver single markers were uniquely associated with serum liver injury indices. BA immune profile is very complex with no single characteristics that would distinguish it from other liver inflammatory diseases.

Numerous innate immune mechanisms have been shown to be activated during viral infections, including pattern recognition receptors (PRRs) functioning outside and inside the cell along with other sensors promoting the production of interferon and other cytokines. Innate cells, including NK cells, NKT cells, γδ T cells, dendritic cells, macrophages, and even neutrophils, have been shown to respond to viral infections. Several innate humoral responses to viral infections have also been identified. Adaptive immunity includes common cell-mediated immunity (CMI) and humoral responses. Th1, Th2, and Tfh CD4+ T cell responses have been shown to help activate cytotoxic T lymphocytes (CTLs) and to help promote the class switching of antiviral antibodies. Enteroviruses were shown to induce innate immune responses and the tropism of the virus that was mediated through viral attachment proteins (VAPs) and cellular receptors was directly related to the risk of severe disease in a primary infection. Adaptive immune responses include cellular and humoral immunity, and its delay in primary infections underscores the importance of vaccination in ameliorating or preventing severe viral pathogenesis.

Vaso-occlusive pain crisis (VOC) is recognized as a prominent complication of sickle cell disease, accompanied by debilitating pain and serious consequences for patients, making it the primary cause of visits to hospital emergency departments. In the etiology of VOC, the intricate interaction of endothelial cells, hypoxia, inflammation, and the coagulation system is pivotal. Hemoglobin S polymerization under hypoxic conditions leads to the formation of rigid and adhesive red blood cells that interact with vascular endothelial cells and other blood cells, causing occlusion and subsequent inflammation. Hemolysis of red blood cells results in anemia and heightened inflammation, whereas oxidative stress and involvement of the coagulation system further complicate matters. In this review, we strive to examine the pathophysiology of VOC from these mentioned aspects by consolidating findings from various studies, as a comprehensive understanding of the causes of VOC is essential for the development of targeted therapeutic interventions and the prevention and management of pain, ultimately improving the quality of life for patients.

Recent research has uncovered new mechanisms that disrupt the balance between the host and microbes in the middle ear, potentially leading to dysbiosis and chronic suppurative otitis media (CSOM). Dysbiotic microbial communities, including core pathogens such as persister cells, are recognized for displaying cooperative virulence. These microbial communities not only evade the host's immune defenses but also promote inflammation that leads to tissue damage. This leads to uncontrolled disorder and pathogen proliferation, potentially causing hearing loss and systemic complications. In this discussion, we examine emerging paradigms in the study of CSOM that could provide insights into other polymicrobial inflammatory diseases. Additionally, we underscore critical knowledge gaps essential for developing a comprehensive understanding of how microbes interact with both the innate and adaptive immune systems to trigger and maintain CSOM.

Oral administration of biologic drugs is challenging because of the degradative activity of the upper gastrointestinal tract. Strategies that use engineered microbes to produce biologics in the lower gastrointestinal tract are limited by competition with resident commensal bacteria. Here we demonstrate the engineering of bacteriophage (phage) that infect resident commensals to express heterologous proteins released during cell lysis. Working with the virulent T4 phage, which targets resident, nonpathogenic Escherichia coli, we first identify T4-specific promoters with maximal protein expression and minimal impact on T4 phage titers. We engineer T4 phage to express a serine protease inhibitor of a pro-inflammatory enzyme with increased activity in ulcerative colitis and observe reduced enzyme activity in a mouse model of colitis. We also apply the approach to reduce weight gain and inflammation in mouse models of diet-induced obesity. This work highlights an application of virulent phages in the mammalian gut as engineerable vectors to release therapeutics from resident gut bacteria.

Allergic and autoimmune disorders are characterised by dysregulation of the immune responses to otherwise inert environmental substances and autoantigens, leading to inflammation and tissue damage. Their incidence has constantly increased in the last decades, and their co-occurrence defies current standards in patient care. For years, allergy and autoimmunity have been considered opposite conditions, with IgE and Th2 lymphocytes cascade driving canonical allergic manifestations and Th1/Th17-related pathways accounting for autoimmunity. Conversely, growing evidence suggests that these conditions not only share some common inciting triggers but also are subtended by overlapping pathogenic pathways. Permissive genetic backgrounds, along with epithelial barrier damage and changes in the microbiome, are now appreciated as common risk factors for both allergy and autoimmunity. Eosinophils and mast cells, along with autoreactive IgE, are emerging players in triggering and sustaining autoimmunity, while pharmacological modulation of B cells and Th17 responses has provided novel clues to the pathophysiology of allergy. By combining clinical and therapeutic evidence with data from mechanistic studies, this review provides a state-of-the-art update on the complex interplay between allergy and autoimmunity, deconstructing old dichotomic paradigms and offering potential clues for future research.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Sorafenib is the first FDA-approved systemic therapy for advanced HCC. This study investigates the influence of IL-23R (rs7517847) and ATG-10 (rs10514231) genetic polymorphisms on Sorafenib response, survival outcomes, average tolerable dose, and adverse events. This prospective open-label cohort study included 100 HCC patients, assessing IL-23R and ATG-10 genotypes via real-time polymerase chain reaction (RT-PCR). Patient's responses were evaluated using modified RECIST criteria. Statistical analyses evaluated the association of genetic variants with response, progression-free survival (PFS), overall survival (OS), average tolerable Sorafenib dose, and adverse events. IL-23R TT carriers had the highest Sorafenib response rate (80%) compared to GT (13.3%) and GG (6.7%) (P = 0.021), while ATG-10 TT carriers had a 13.9-fold increased response likelihood (P = 0.001). The T allele in ATG-10 significantly predicted longer PFS (P = 0.025) and OS (P = 0.011), suggesting a potential prognostic role. IL-23R GG carriers received significantly higher Sorafenib doses than TT (P = 0.0174) and GT (P = 0.0227), whereas ATG-10 had no effect on dosage. However, its CT genotype was significantly associated with a higher risk of Hand-Foot Syndrome (P = 0.012), and independent of dose (P = 0.0018). IL-23R and ATG-10 polymorphisms influence Sorafenib response, survival, and tolerability in HCC patients. Genetic screening may improve personalized treatment strategies by optimizing Sorafenib efficacy and minimizing toxicity.This trial was registered on clinicaltrials.gov with registration number NCT06030895, registered on "September 11th, 2023," retrospectively.

Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ spatiotemporally controlled oncogene activation and tumor suppressor inhibition together with multiomics to unveil the processes underlying oral epithelial progenitor cell reprogramming into tumor initiating cells at single cell resolution. Tumor initiating cells displayed a distinct stem-like state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal invasive gene programs. YAP-mediated tumor initiating cell programs included activation of oncogenic transcriptional networks and mTOR signaling, and recruitment of myeloid cells to the invasive front contributing to tumor infiltration. Tumor initiating cell transcriptional programs are conserved in human head and neck cancer and associated with poor patient survival. These findings illuminate processes underlying cancer initiation at single cell resolution, and identify candidate targets for early cancer detection and prevention.

Severe asthma is a critical condition for patients with asthma, characterized by frequent exacerbations, decreased pulmonary function, and unstable symptoms related to asthma. Consequently, the administration of systemic corticosteroids, which cause secondary damage because of their adverse effects, is considered. Recently, several types of molecular-targeted biological therapies have become available for patients with severe asthma, and they have a capacity to improve the pathophysiology of severe asthma. However, several clinical reports indicate that the effects differ depending on the biological targets of asthma in individual patients. In this review, the molecular mechanisms and clinical impact of biologic therapies in severe asthma are described. In addition, molecules targeted by possible future biologics are also addressed. Better understanding of the mechanistic basis for the role of biologics in severe asthma could lead to new therapeutic options for these patients.

Although there have been reports on the association between smoking and increased level of inflammatory markers in hypertensive this has not been assessed prospectively in a large, modern cohort using data mining approaches. We conducted a cross-sectional analysis of the Mashad trial which was a prospective. 2085 smokers aged 35 to 65 years was studied. Inflammatory indices measured included: Hemoglobin-Platelet Ratio (HPR), Uric acid-high Density Lipoprotein (HDL) Ratio (UHR), Neutrophil-Lymphocyte Ratio (NLR), Systemic Immune Inflammation (SII) index, WBC, Platelet-Lymphocyte Ratio (PLR), and RBC Distribution Width (RDW). The association between these parameters and smoking in hypertensive individuals was examined. Over the course of the 6-year monitoring period, 585 peoples had HTN of whom the majority was female (59%). As per the LR analysis, there was a significant association between hypertension and age, WBC, SII, PLR in female smokers, as well as age and PLR in male smokers. (p-value < 0.05). PLR (OR = 0.993, CI 95% (0.987, 0.999)) and age (1.080 (1.058, 1.102)) for male and WBC (1.340 (1.139, 1.577)) and age (1.091 (1.070, 1.113)) for female exhibits the most appropriate estimate. Using the DT model for male individuals, those with, age ≥ 64 years, and SII < 336 had the correlated with hypertension prevalence (76%). For females, those with age ≥ 62 years, WBC ≥ 6.1, and SII < 445.634 had the highest risk of HTN. Age and SII for smoker males and age and WBC for smoker females showed the strongest correlation with hypertension. Age and WBC were the most significant indicators for predicting HTN.

Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated exceptional efficacy against hematological malignancies, but notably less against solid tumors. To overcome this limitation, it is critical to investigate antitumor CAR-T cell potency in synthetic 3D microenvironments that can simulate the physical barriers presented by solid tumors. The overall goal of this study was the preliminary assessment of a synthetic thermo-responsive material as a substrate for in vitro co-cultures of anti-disialoganglioside (GD2) CAR-T cells and patient-derived glioblastoma (GBM) spheroids. Independent co-culture experiments demonstrated that the encapsulation process did not adversely affect the cell cycle progression of glioma stem cells (GSCs) or CAR-T cells. GSC spheroids grew over time within the terpolymer scaffold, when seeded in the same ratio as the suspension control. Co-cultures of CAR-T cells in suspension with hydrogel-encapsulated GSC spheroids demonstrated that CAR-T cells could migrate through the hydrogel and target the encapsulated GSC spheroids. CAR-T cells killed approximately 80% of encapsulated GSCs, while maintaining effective CD4:CD8 T cell ratios and secreting inflammatory cytokines after interacting with GD2-expressing GSCs. Importantly, the scaffolds also facilitated cell harvesting for downstream cellular analysis. This study demonstrated that a synthetic 3D terpolymer hydrogel can serve as an artificial scaffold to investigate cellular immunotherapeutic potency against solid tumors.

Mycobacterium bovis (M. bovis) is the primary agent of bovine tuberculosis (TB) in Mediterranean buffalo, which has a negative economic impact on buffalo herds. Improving TB diagnostic performance in this species represents a key step to eradicate efficiently this disease. We have recently shown the utility of the IFN-γ assay in the diagnosis of M. bovis infection in Mediterranean buffaloes (Bubalus bubalis), but other cytokines might be useful immunological biomarkers of this infection. We therefore investigated the utility of key immune cytokines as diagnostic biomarkers of M. bovis infection in this species. Thirty-six Italian Mediterranean buffaloes were used in this study: healthy animals (N = 11), infected (IFN-γ test positive, no post-mortem lesions, no M. bovis detection; N = 14), and affected (IFN-γ test positive, visible post-mortem lesions; N = 11). Heparin blood samples were stimulated with bovine purified protein derivative (PPD-B), alongside controls, and 18-24 h later plasma were collected. Levels of 14 key cytokines were measured: IFN-γ, IL-17, IL-4, IL-10, TNF, IL-1α, IL-1β, IL-6, IP-10, MIP-1α, MIP-1β, MCP-1, IL-36Ra, and VEGF-A. We observed that both infected and affected animals released higher levels of IFN-γ, IL-17, IL-10, TNF, IL-1α, IL-6, MIP-1β, in response to PPD-B compared to healthy subjects. Mycobacterium bovis infected animals released also higher levels of IL-1β and IP-10 in response to PPD-B compared to healthy subjects, whereas only tendencies were detected in affected animals. Affected animals only released MIP-1α in response to PPD-B compared to healthy subjects and in this group higher values of PPD-B specific TNF was also observed. Finally, canonical discriminant analysis (CDA) was used to generate predictive cytokine profiles by groups. Our data suggest that IL-10, TNF, IL-1α, IL-6, MIP-1β could be useful biomarkers of TB in Mediterranean Buffalo and can improve the TB diagnostic performance in this specie.

Stachys byzantina is a plant widely cultivated for food and medicinal purposes. Stachys species have been reported as anti-inflammatory, antibacterial, anxiolytic, and antinephritic agents. This study aimed to evaluate the anti-inflammatory potential of the ethanolic extract (EE) from the aerial parts of S. byzantina and its most promising fraction in models of acute and chronic inflammation, including a psoriasis-like mouse model. The EE was fractionated into hexane (HF), dichloromethane (DF), ethyl acetate (AF), and hydroalcoholic (HD) fractions. Screening for anti-inflammatory activity based on nitric oxide inhibition (IC50 μg/mL: HF 24.29 ± 5.87, EE 176.45 ± 18.65), hydroxyl radical scavenging (HF 3.89 ± 0.61, EE 6.38 ± 2.25), β-carotene/linoleic acid assay (HF 10.13 ± 3.81, EE 25.64 ± 2.12), and ORAC identified HF as the most active fraction. Topical application of HF effectively reduced croton oil- and phenol-induced ear edema in mice, with no statistical difference to the reference drugs. A formulation containing HF showed significant activity in the imiquimod-induced psoriasis model, reducing pro-inflammatory cytokines and nitric oxide production in macrophages, with no cytotoxicity to skin cells. Phytochemical analysis of HF revealed the presence of terpenes, steroids (491.68 ± 4.75 mg/g), phenols (34.30 ± 4.96 mg/g), flavonoids (151.77 ± 6.66 mg/g), and α-tocopherol, which was identified and quantified by HPLC-UV analysis (10.56 ± 0.97 mg/g of HF). These findings highlight the therapeutic potential of S. byzantina for skin inflammation, particularly contact dermatitis and psoriasis, encouraging further studies, including in human volunteers.

Obstructive sleep apnoea (OSA) is a long-term disorder characterized by frequent blockages in the upper respiratory tract during sleep, often leading to abrupt awakenings, with or without a decrease in oxygen levels. The systematic review and meta-analysis aimed to assess the effect of continuous positive airway pressure therapy (CPAP) on blood interleukin (IL) levels of IL-6, IL-10, IL-18, IL-1β, IL-4, and IL-17 in OSA adults.

The published databases from PubMed, Scopus, Web of Science, and Cochrane Library were searched from 2003 to 2024, without any restrictions. The Review Manager software 5.3 was employed to compute effect sizes, which were presented as the standardized mean difference (SMD) along with a 95% confidence interval (CI).

In total, 320 records were identified through database searching; ultimately, 42 articles were included in the qualitative synthesis and then the meta-analysis. The CPAP therapy significantly reduces IL-6 levels, as indicated SMD=0.64 [95% CI: 0.35, 0.93] and P<0.0001. CPAP therapy significantly reduced IL-18 and IL-1β levels in adults with OSA, but there is no significant difference in IL-10, IL-4, or IL-17 levels. Age, blood sample, body mass index, ethnicity, and treatment duration for IL-6 and apnoea-hypopnea index with IL-10 levels were effective factors in the pooled results. Experimentally, there was an interaction between IL-18 and IL-1β.

CPAP therapy has a positive impact on inflammatory markers in OSA adults; remarkably, it reduces IL-6 and IL-1β levels. Nevertheless, more evidence (such as the role of ethnicity) and understanding of interactions are needed.

The interplay between the dysbiotic microbiota and bile acids is a critical determinant for development of a dysregulated immune system in inflammatory bowel disease (IBD). Here we have investigated the fecal bile acid metabolome, gut microbiota composition, and immune responses in IBD patients and murine models of colitis and found that IBD associates with an elevated excretion of primary bile acids while secondary, allo- and oxo- bile acids were reduced. These changes correlated with the disease severity, mucosal expression of pro-inflammatory cytokines and chemokines, and reduced inflow of anti-inflammatory macrophages and Treg in the gut. Analysis of bile acids metabolome in the feces allowed the identification of five bile acids: 3-oxo-DCA, 3-oxo-LCA, allo-LCA, iso-allo-LCA and 3-oxo-UDCA, whose excretion was selectively decreased in IBD patients and diseased mice. By transactivation assay and docking calculations all five bile acids were shown to act as GPBAR1 agonists and RORγt inverse agonists, skewing Th17/Treg ratio and macrophage polarization toward an M2 phenotype. In a murine model of colitis, administration of 3-oxo-DCA suffices to reverse colitis development and intestinal dysbiosis in a GPBAR1-dependent manner. In vivo administration of 3-oxo-DCA to colitic mice also reverses disease severity and RORγt activation induced by a RORγt agonist and IL-23, a Th17 inducing cytokine. These results demonstrated that intestinal excretion of 3-oxoDCA, a dual GPBAR1 agonist and RORγt inverse agonist, is reduced in IBD and in models of colitis and its restitution protects against colitis development, highlighting a potential role for this agent in IBD management.

Gamma delta T cells play a crucial role in anti-tumor immunity due to their cytotoxic properties. However, the role and extent of γδ T cells in production of pro-tumorigenic interleukin-17 (IL-17) within the tumor microenvironment of colorectal cancer (CRC) remains controversial. In this study, we re-analyzed nine published human CRC whole-tissue single-cell RNA sequencing datasets, identifying 18,483 γδ T cells out of 951,785 total cells, in the neoplastic or adjacent normal tissue of 165 human CRC patients. Our results confirm that tumor-infiltrating γδ T cells exhibit high cytotoxicity-related transcription in both tumor and adjacent normal tissues, but critically, none of the γδ T cell clusters showed IL-17 production potential. We also identified various γδ T cell subsets, including poised effector-like T cells, tissue-resident memory T cells, progenitor exhausted-like T cells, and exhausted T cells, and noted an increased expression of cytotoxic molecules in tumor-infiltrating γδ T cells compared to their normal area counterparts. We proposed anti-tumor γδ T effector cells may arise from tissue-resident progenitor cells based on the trajectory analysis. Our work demonstrates that γδ T cells in CRC primarily function as cytotoxic effector cells rather than IL-17 producers, mitigating the concerns about their potential pro-tumorigenic roles in CRC, highlighting the importance of accurately characterizing these cells for cancer immunotherapy research and the unneglectable cross-species discrepancy between the mouse and human immune system in the study of cancer immunology.

Chimeric antigen receptor (CAR)-T-cell therapy has emerged as a powerful weapon in the fight against cancer. However, its efficacy is often hindered by challenges such as limited tumor penetration, antigen escape, and immune suppression within the tumor microenvironment. This review explores the potential of armored CAR-T cells, or 'micropharmacies', in overcoming these obstacles and enhancing the therapeutic outcomes of adoptive T-cell (ATC) therapy. We delve into the engineering strategies behind these advanced therapies and the mechanisms through which they improve CAR-T-cell efficacy. Additionally, we discuss the latest advancements and research findings in the field, providing a comprehensive understanding of the role of armored CAR-T cells in cancer treatment. Ultimately, this review highlights the promising future of integrating micropharmacies into ATC therapy, paving the way for more effective and targeted cancer treatments.

We present the first case of a dupilumab-induced hyperinflammatory state in the setting of underlying eosinophilic esophagitis characterized by multisystem granulomatous inflammation. Although clinical trial data and subsequent real-world experience support dupilumab as a highly effective therapy for eosinophilic esophagitis, close monitoring for development of adverse symptoms following initiation remains paramount.

Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ spatiotemporally controlled oncogene activation and tumor suppressor inhibition together with multiomics to unveil the processes underlying oral epithelial progenitor cell reprogramming into tumor initiating cells (TIC) at single cell resolution. TIC displayed a distinct stem-like state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal (pEMT) invasive gene programs. YAP-mediated TIC programs included the activation of oncogenic transcriptional networks and mTOR signaling, and the recruitment of myeloid cells to the invasive front contributing to tumor infiltration. TIC transcriptional programs are conserved in human head and neck cancer and associated with poor patient survival. These findings illuminate processes underlying cancer initiation at single cell resolution, and identify candidate targets for early cancer detection and prevention.

Psoriatic arthritis (PsA) is a debilitating chronic condition characterized by inflammation of the joints, bones, enthesis, and skin. The pivotal role of interleukin-23 (IL-23) in the pathogenesis of PsA has become increasingly evident. This proinflammatory cytokine is markedly elevated in patients with PsA, suggesting its potential as a therapeutic target. Consequently, IL-23 inhibitors have emerged as promising first-line biologic treatments for PsA.

This review delves into the immunopathogenic mechanisms of IL-23 at the cellular and molecular levels in PsA. Furthermore, it provides the recent efficacy and safety profiles of IL-23 inhibitors. We conducted a literature search in PubMed for the following terms: 'IL-23 and psoriatic arthritis,' 'Ustekinumab,' 'Guselkumab,' 'Risankizumab,' and 'Tildrakizumab.' In addition, we retrieved clinical trials involving IL-23 inhibitors registered in ClinicalTrials.gov, EudraCT, and ICTRP.

Despite the promising outcomes observed with IL-23 inhibitors, several challenges persist. The long-term effects of these agents require further investigation through prospective studies, and their limited accessibility worldwide necessitates urgent attention. Additionally, ongoing research is warranted to explore other potential drug targets within the IL-23/IL-23 R axis. The development of reliable biomarkers could greatly enhance early detection, tailored management strategies, and personalized treatment approaches for patients with PsA.

Wounds are the common fates in various microbial infections and physical damages including accidents, surgery, and burns. In response, a healthy body with a potent immune system heals that particular site within optimal time by following the coagulation, inflammation, proliferation, and remodeling phenomenon. However, certain malfunctions in the body due to various diseases particularly diabetes and other physiological factors like age, stress, etc., prolong the process of wound healing through various mechanisms including the Akt, Polyol, and Hexosamine pathways. The current review thoroughly explains the wound types, normal wound healing mechanisms, and the immune system's role. Moreover, the mechanistic role of diabetes is also elaborated comprehensively.

Psoriasis is an incurable immune-mediated skin disease, affecting around 1%-3% of the population. Various lines of evidence implicate IL23 as being pivotal in disease. Genetic variants within the IL23 receptor (IL23R) increase the risk of developing psoriasis, and biologic therapies specifically targeting IL23 demonstrated high efficacy in treating disease. IL23 acts via the IL23R, signalling through the STAT3 pathway, mediating the cascade of events that ultimately results in the clinical presentation of psoriasis. Given the essential role of IL23R in disease, it is important to understand the impact of genetic variants on receptor function with respect to downstream gene regulation. Here we developed model systems in CD4+ (Jurkat) and CD8+ (MyLa) T cells to express either the wild type risk or mutant (R381Q) protective form of IL23R. After confirmation that the model system expressed the genes/proteins and had a differential effect on the phosphorylation of STAT3, we used RNAseq to explore differential gene regulation, in particular for genes implicated with risk to psoriasis, at a single time point for both cell types, and in a time course experiment for Jurkat CD4+ T cells. These experiments discovered differentially regulated genes in the cells expressing wild type and mutant IL23R, including HLA-B, SOCS1, RUNX3, CCR5, CXCR3, CCR9, KLF3, CD28, IRF, SOCS6, TNFAIP and ICAM5, that have been implicated in both the IL23 pathway and psoriasis. These genes have the potential to define a IL23/psoriasis pathway in disease, advancing our understanding of the biology behind the disease.

The elastomechanical properties of nanocarriers have recently been discussed as important for the efficient delivery of various therapeutics. Some data indicate that optimal nanocarriers' elasticity can modulate in vivo nanocarrier stability, interaction with phagocytes, and uptake by target cells. Here, we presented a study to extensively analyze the in vivo behavior of LIP-SS liposomes that were modified by forming the silicone network within the lipid bilayers to improve their elastomechanical properties. We verified liposome pharmacokinetic profiles and biodistribution, including retention in tumors on a mouse model of breast cancer, while biocompatibility was analyzed on healthy mice.

We showed that fluorescently labeled LIP-SS and control LIP-CAT liposomes had similar pharmacokinetic profiles, biodistribution, and retention in tumors, indicating that modified elasticity did not improve nanocarrier in vivo performance. Interestingly, biocompatibility studies revealed no changes in blood morphology, liver, spleen, and kidney function but indicated prolonged activation of immune response manifesting in increased concentration of proinflammatory cytokines in sera of animals exposed to all tested liposomes.

Incorporating the silicone layer into the liposome structure did not change nanocarriers' characteristics in vivo. Further modification of the LIP-SS surface, including decoration with hydrophilic stealth polymers, should be performed to improve their pharmacokinetics and retention in tumors significantly. Activation of the immune response by LIP-SS and LIP-CAT, resulting in elevated inflammatory cytokine production, requires detailed studies to elucidate its mechanism.

The advent of biological therapies has already revolutionized treatment strategies and disease course of several rheumatologic conditions, and monoclonal antibodies (mAbs) targeting cytokines and interleukins represent a considerable portion of this family of drugs. In systemic lupus erythematosus (SLE) dysregulation of different cytokine and interleukin-related pathways have been linked to disease development and perpetration, offering palatable therapeutic targets addressable via such mAbs.

In this review, we provide an overview of the different biological therapies under development targeting cytokines and interleukins, with a focus on mAbs, while providing the rationale behind their choice as therapeutic targets and analyzing the scientific evidence linking them to SLE pathogenesis.

An unprecedented number of clinical trials on biological drugs targeting different immunological pathways are ongoing in SLE. Their success might allow us to tackle present challenges of SLE management, including the overuse of glucocorticoids in daily clinical practice, as well as SLE heterogenicity in treatment response among different individuals, hopefully paving the way toward precision medicine.

Influenza infections result in a significant number of severe illnesses annually, many of which are complicated by secondary bacterial super-infection. Primary influenza infection has been shown to increase susceptibility to secondary methicillin-resistant Staphylococcus aureus (MRSA) infection by altering the host immune response, leading to significant immunopathology. Type III interferons (IFNs), or IFNλs, have gained traction as potential antiviral therapeutics due to their restriction of viral replication without damaging inflammation. The role of IFNλ in regulating epithelial biology in super-infection has recently been established; however, the impact of IFNλ on immune cells is less defined. In this study, we infected wild-type and IFNLR1-/- mice with influenza A/PR/8/34 followed by S. aureus USA300. We demonstrated that global IFNLR1-/- mice have enhanced bacterial clearance through increased uptake by phagocytes, which was shown to be cell-intrinsic specifically in myeloid cells in mixed bone marrow chimeras. We also showed that depletion of IFNLR1 on CX3CR1 expressing myeloid immune cells, but not neutrophils, was sufficient to significantly reduce bacterial burden compared to mice with intact IFNLR1. These findings provide insight into how IFNλ in an influenza-infected lung impedes bacterial clearance during super-infection and show a direct cell intrinsic role for IFNλ signaling on myeloid cells.

To explore severity and progression biomarkers, we examined the clinical relevance of multiple cytokines and mediators involved in the inflammatory response in periodontitis. A cohort of 68 patients was enrolled in the study and periodontal status assessed by the current classification of periodontal diseases. Immune mediators present in saliva, of both patients and healthy controls, were quantified using a Legendplex-13 panel. Clinic parameters were significantly higher in PD patients compared with HC, with a strong significant association with the disease severity (stage) (p < 0.001), but not with progression (grade). The panel of immune mediators evidenced elevated levels of pro-inflammatory cytokines IL-6 and IL-1β as disease established (p < 0.01). IL-1β/IL-1RA ratio was increased in PD patients, being associated with disease stage. An anti-inflammatory response was spotted by higher IL-10. Lower levels of IL-23 and IP-10 were associated with disease severity. No significant statistical differences were found by grade classification. Moreover, salivary IL-1β and IL-6 exhibited significant positive correlations with several clinical measurements (PI, BOP, PPD, CAL), while IP-10 showed a statistical negative correlation with BOP, PPD, and CAL. These insights highlight the complexity of the periodontitis inflammatory network and the potential of cytokines as biomarkers for refined diagnostic and therapeutic strategies.

Primary membranous nephropathy (PMN), an autoimmune disease, is the most common cause of nephrotic syndrome in middle-aged non-diabetic adults. PMN pathophysiology includes Th1/Th2 paradigm. The IL-23/IL-17 pathway is implicated in autoimmune kidney disorders, but no study has examined its relationship with PMN. In several unrelated studies, PMN patients reported to have paradoxical IL-17 levels. This manuscript describes the best possible association of IL-23/IL-17 axis with PMN. Biopsy-proven PMN patients and age, gender-matched healthy controls were enrolled. Serum-PLA2R (Euroimmune, Germany), IL-23 and IL-17 (R&D; USA), was measured using ELISA along with biochemical parameters. Appropriate statistical tools were used for analysis. One hundred eighty-nine PMN patients (mean age 41.70 ± 12.53 years) and 100 controls (mean age 43.92 ± 10.93 years) were identified. One hundred forty were PLA2R-related. PMN patients had median proteinuria, serum albumin, and creatinine of 6.12 (3.875, 9.23) g/day, 2.32 (1.96, 2.9) g/dl, and 0.89 (0.7, 1.1) mg/dl, respectively. IL-17, but not IL-23, was significantly increased in PMN patients compared to controls (IL-17, median: 12.07 pg/ml (9.75, 24.56) vs median: 9.75 pg/ml (8.23, 17.03) p = 0.0002); (IL23, median: 6.04 pg/ml (4.22, 10.82) vs median: 5.46 pg/ml (3.34, 9.96) p = 0.142). IL-17 and IL-23 correlated significantly (p 0.05) in PMN patients, and similar trend was seen when grouped into PLA2R-related and -unrelated groups. The levels of IL-23 (p = 0.057) and IL-17 (p = 0.004) were high in MN patients that did not respond to the treatment. The current finding may indicate or suggest the involvement of IL-23/IL-17 PMN pathogenesis. A comprehensive investigation is needed to evaluate IL-23/IL-17 axis with renal infiltrating immune cells, and external stimuli.

Psoriasis is a chronic inflammatory systemic disease accompanied by systemic damage that leads to the development of multiple comorbidities including metabolic syndrome. Conventional systemic therapies for psoriasis are associated with toxicity and have a greater burden on the patients. The study aimed to assess the effectiveness of etanercept (ETN) monotherapy in comparison with methotrexate (MTX) monotherapy.

In this prospective interventional comparative open-label study, 117 patients with psoriasis were randomized to 2 groups; 1 group of 42 patients; 32 (67.2%) males and 10 (23.8%) females treated with MTX, and the second group of 75 patients; 54 (72%) males and 21 (28%) females treated with ETN. Full laboratory investigations, body mass index (BMI), measurement of skin disease severity which was performed using Psoriasis Area Severity Index (PASI), and the reduction of 75% of the skin lesions (PASI 75) were calculated for all participants.

In the MTX group, there were no significant differences in BMI, or blood pressure after 12 weeks of the study. There is a reduction in the values of FBS, TSC, LDL, TRIG, ESR, CRP, and PASI, but this reduction was statistically not significant. Ten (23.8%) patients achieved PASI 75. In the ETN group, except for BMI, systolic and diastolic blood pressure, all other metabolic syndrome components, inflammatory markers, and PASI were decreased; the reduction was statistically significant. Sixty (80%) patients achieved PASI 75.

Etanercept monotherapy showed greater efficacy than MTX monotherapy in the treatment of moderate to severe plaque-type psoriasis as it achieved greater reductions in PASI score and greater achievement of PASI 75 after 12 weeks. Etanercept monotherapy showed greater efficacy than MTX monotherapy in the improvement of all components of the associated metabolic syndrome except for BMI, which was increased in etanercept-treated patients.

Gamma delta (γδ) T cells play a crucial role in anti-tumor immunity due to their cytotoxic properties. However, the role and extent of γδ T cells in production of pro-tumorigenic interleukin- 17 (IL-17) within the tumor microenvironment (TME) of colorectal cancer (CRC) remains controversial. In this study, we re-analyzed nine published human CRC whole-tissue single-cell RNA sequencing (scRNA-seq) datasets, identifying 18,483 γδ T cells out of 951,785 total cells, in the neoplastic or adjacent normal tissue of 165 human CRC patients. Our results confirm that tumor-infiltrating γδ T cells exhibit high cytotoxicity-related transcription in both tumor and adjacent normal tissues, but critically, none of the γδ T cell clusters showed IL-17 production potential. We also identified various γδ T cell subsets, including Teff, TRM, Tpex, and Tex, and noted an increased expression of cytotoxic molecules in tumor-infiltrating γδ T cells compared to their normal area counterparts. Our work demonstrates that γδ T cells in CRC primarily function as cytotoxic effector cells rather than IL-17 producers, mitigating the concerns about their potential pro-tumorigenic roles in CRC, highlighting the importance of accurately characterizing these cells for cancer immunotherapy research and the unneglectable cross-species discrepancy between the mouse and human immune system in the study of cancer immunology.

In recent times, the pathogenesis of generalized anxiety disorder (GAD) and the influence of pro- and anti-inflammatory cytokines on it have garnered considerable interest. Cytokine research, especially Th-17 cytokine research on GAD patients, is limited. Here, we aim to assess the role of interleukin-17A (IL-17A) and interleukin-23A (IL-23A) in the pathophysiology and development of GAD. This investigation included 50 GAD patients and 38 age-sex-matched healthy controls (HCs). A psychiatrist diagnosed patients with GAD and assessed symptom severity using the DSM-5 and the GAD-7 scales. The serum concentrations of IL-17A and IL-23A were determined using commercially available ELISA kits. GAD patients exhibited elevated levels of IL-17A (77.14 ± 58.30 pg/ml) and IL-23A (644.90 ± 296.70 pg/ml) compared to HCs (43.50 ± 25.54 pg/ml and 334.40 ± 176.0 pg/ml). We observed a positive correlation between disease severity and cytokine changes (IL-23A: r = 0.359, p = 0.039; IL-17A: r = 0.397, p = 0.032). These findings indicate that IL-17A and IL-23A may be associated with the pathophysiology of GAD. ROC analysis revealed moderately higher AUC values (IL-23A: 0.824 and IL-17A: 0.710), demonstrating their potential to discriminate between patients and HCs. Also, the sensitivity values of both cytokines were relatively higher (IL-23A: 80.49% and IL-17A: 77.27%). According to the present findings, there may be an association between peripheral serum levels of IL-17A and IL-23A and the pathophysiology and development of GAD. These altered serum IL-17A and IL-23A levels may play a role in directing the early risk of developing GAD. We recommend further research to ascertain their exact role in the pathophysiology and their performance as risk assessment markers of GAD.

Acrylamide (ACR), an industrial compound, causes both male and female reproductive toxicity. Lepidium sativum seeds (L. sativum) (Garden cress) are known for their health benefits as antioxidant, antiasthmatic, anticoagulant, anti-inflammatory, and analgesic agents. Therefore, this study aimed to investigate the phytochemistry and nutritional value of L. sativum seeds oil for attenuating the ovarian damage induced by acrylamide in rats. The phytochemical investigation of the seeds revealed the presence of vitamins, potassium, iron, sugar and amino acids. Twenty eight compounds from the unsaponifiable fraction and twenty three compounds from the saponifiable fraction were identified. Three sterols and two triterpenes were isolated and identified as β-sitosterol (1), ▵5-avenasterol (2), friedelanol (3), stigmasta-4, 22-dien-3-one (4), and ursolic acid (5). Treatment of acrylamide-induced rats with L. sativum seeds oil ameliorated prolactin (PRL), progesterone (P4), estradiol (E2), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF- α) with variable degrees. The histopathological findings of ovaries supported these results. In conclusion, compounds (3-5) were isolated for the first time from L. sativum seeds oil. The seeds oil attenuated the ovarian damage and could potentially be a new supplemental agent against female infertility.

Inflammatory bowel disease (IBD) is a medical condition that causes persistent, relapsing inflammation of the gastrointestinal tract. It is an umbrella term encompassing two different conditions: ulcerative colitis (UC) and Crohn's disease (CD). The standard treatment for patients with moderate to severe CD is tumor necrosis factor-α (TNF-α) inhibitors; however, a subset of CD patients face challenges in regard to this disease's treatment. Certain populations of patients with CD may exhibit resistance or develop tolerance to TNF-α inhibitor therapy over time. The recurrent gastrointestinal inflammation associated with CD can severely impact the quality of life and lead to complications for those suffering from this condition. The symptomatic flare-ups these subpopulations continue to experience underscores why such a need for alternative therapies is desperately needed. These alternative therapies not only offer potential benefits for those with TNF-α resistance, but CD may also serve as a superior therapy option for those trying to avoid the adverse effects of CD treatments available today. This review aims to explore and investigate the novel drugs and therapies that are being investigated for the treatment of TNF-α resistant CD, such as upadacitinib, risankizumab, vedolizumab, synbiotics, fecal microbiota transplantation (FMT), and stem cell therapy. Upadacitinib is a Janus kinase inhibitor, Risankizumab is a monoclonal antibody targeting interleukin-23, and Vedolizumab is an integrin receptor antagonist. The latest advancements in CD management have shown encouraging results. Some of these novel drugs and therapies not only offer a potential solution for CD patients exhibiting resistance to TNF-α inhibitors but may also provide a superior alternative for individuals prone to opportunistic infections.

This review highlights advances made in psoriasis genetics, including findings from genome-wide association studies, exome-sequencing studies, and copy number variant studies. The impact of genetic variants on various comorbidities and therapeutic responses is discussed.

Ulcerative colitis (UC) is a complicated and recurrent intestinal disease. Currently available drugs for UC treatment are scarce, therefore, novel therapeutic drugs for the UC are urgently to be developed. Gingerenone A (GA) is a phenolic compound known for its anti-inflammatory effect, but its effect on UC remains unknown. Here, it is shown that GA protects mice against UC, which is closely associated with inhibiting intestinal mucosal inflammation and enhancing intestinal barrier integrity in vivo and in vitro. Of note, RNA sequencing analysis demonstrates an evident correlation with IL-17 signaling pathway after GA treatment, and this effect is further corroborated by Western blot. Mechanistically, GA directly interacts with IL-17RA protein through pull-down, surface plasmon resonance analysis and molecular dynamics simulation. Importantly, lentivirus-mediated IL-17RA/Act1 knock-down or GA co-treatment with brodalumab/ixekizumab significantly impairs the protective effects of GA against DSS-induced inflammation and barrier dysfunction, suggesting a critical role of IL-17RA signaling for GA-mediated protection against UC. Overall, these results indicate that GA is an effective agent against UC mainly through the direct binding of IL-17RA to inhibit inflammatory signaling activation.