Search Results (95)

Peri-implantitis is characterized by progressive tissue destruction accompanied by dysregulated innate and adaptive immune responses. This study evaluated whether systemic treatment with 2-deoxy-D-glucose (2-DG) could attenuate experimental peri-implantitis and alter inflammatory markers associated with macrophage- and T-cell-mediated responses in a rat model. Experimental peri-implantitis was induced in Sprague–Dawley rats by Porphyromonas gingivalis-inoculated silk ligation around the implant neck. After disease induction, animals received intraperitoneal injections of 2-DG or normal saline for six weeks while ligature-associated challenge was maintained. Peri-implant tissues were assessed by micro-computed tomography (micro-CT), hematoxylin and eosin staining, immunohistochemistry (IHC), and reverse transcription-quantitative PCR (RT-qPCR). 2-DG treatment significantly reduced peri-implant bone resorption and was associated with less pronounced bone-resorptive morphology. RT-qPCR showed lower expression of M1-associated genes (CD86, iNOS, TNF-α, IL-6, and IL-18) and the Th17-associated genes IL-17 and RORγT, whereas IL-21, M2-associated genes, and the Treg-associated gene FOXP3 were not significantly changed. IHC showed qualitative trends toward lower iNOS- and IL-17-positive signals. These findings provide proof-of-concept evidence that 2-DG treatment reduces peri-implant bone loss and is associated with attenuated inflammatory changes and lower expression of M1- and Th17-associated inflammatory markers in experimental peri-implantitis. This study supports further investigation of 2-DG as a potential immunometabolic adjunct for peri-implantitis management. Full article

Background: Allergic rhinitis (AR) is a chronic condition that affects children’s quality of life. Studies show that adding bacterial lysates (BLs) to treatment can improve outcomes, but their effects on the immune system are still not fully understood. Objectives: This study aimed to evaluate the immunomodulatory impact of sublingually administered polyvalent mechanical BL (PMBL) on the expression of T helper (Th) cell-associated transcription factors and cytokines in children with grass pollen-induced AR. Methods: Immunological analyses were performed on blood samples collected during a previously conducted randomised, double-blind, placebo-controlled clinical trial (NCT04802616). Children aged 5–17 years with grass pollen-induced AR received either sublingual PMBL or placebo in three 10-day treatment cycles, each followed by a 20-day break. Peripheral blood mononuclear cells were collected at baseline before the grass pollen season (V1) and after completion of the study treatment during natural peak pollen exposure (V2) and analysed by flow cytometry to assess the expression of transcription factors and cytokines associated with Th1, Th2, Th10, Th17, and Treg-like immune responses. Results: In the PMBL group, there was a significant increase in the expression of T-bet, E4BP4, FoxP3, IFN-γ, and IL-10, along with a reduction in GATA3 and IL-4 expression (p < 0.001). The placebo group exhibited increased expression of GATA3 (p < 0.001), RORγT (p < 0.001), and IL-4 (p = 0.004) and a reduction in T-bet expression (p = 0.007). Between-group comparisons at V2 revealed significantly higher expression of Th1-, Th10-, and Treg-associated markers, and lower Th2- and Th17-associated markers in the PMBL group compared to placebo. Conclusions: Sublingual PMBL administration modulates the expression of Th cell-associated transcription factors and cytokines in children with grass pollen-induced AR, consistent with enhanced Th1-, Th10-, and Treg-like immune responses and reduced Th2-associated activity. Full article

Allergic asthma is associated with a reduction in the number of regulatory T cells (Tregs). Although interleukin-27 (IL-27) has been shown to modulate Tregs potentially through the Lymphocyte-activation gene 3 (Lag3) pathway, the underlying mechanism remains incompletely defined. Objective: This study sought to determine whether IL-27 ameliorates airway inflammation in asthma by modulating Tregs in a Lag3-dependent manner. Acute asthma was induced in wild-type (WT) and Lag3 knockout (Lag3^−/−) mice through sensitization and challenge with house dust mite (HDM). A treatment group received intranasal recombinant IL-27 prior to challenges. In WT mice, IL-27 administration significantly attenuated airway inflammation, goblet cell hyperplasia, and total cell counts in bronchoalveolar lavage fluid (BALF), along with reduced levels of Th2 cytokines (IL-4, IL-5). It also upregulated T-bet (Th1) mRNA expression, downregulated GATA-3 (Th2) and RORγt (Th17) levels, and increased the proportions of CD4⁺ Foxp3⁺ Tregs, CTLA4⁺ Tregs, and Lag3⁺ Tregs in lung tissue. Conversely, in Lag3^−/− mice, the protective effects of IL-27 were completely abrogated, with no observed increases in Treg populations or suppression of Th2/Th17 immune responses. The anti-asthmatic effect of exogenous IL-27 is associated with increased Treg frequency and upregulation of inhibitory markers, with Lag3 serving as a pivotal target on Tregs. Full article

Interleukin-17A (IL-17A) is a proinflammatory cytokine that plays a pivotal role in immune responses and tissue homeostasis. Its expression is strictly regulated by transcription factors including RORγt, and it is mainly produced by Th17 cells, γδ T cells, and innate lymphoid cells. IL-17A signals through a heterodimeric receptor complex consisting of IL-17RA and IL-17RC, activating NF-κB, MAPK, and C/EBP pathways via the adaptor protein Act1. IL-17 signaling is counterbalanced by negative regulators including A20 and Regnase-1. Beyond its classical roles in antimicrobial defense and autoimmune inflammation, recent studies have highlighted its functions in the central nervous system, with associations to multiple sclerosis, autism spectrum disorder, and Alzheimer’s disease. The development of IL-17A inhibitors, including the dual IL-17A/F antagonist bimekizumab, has advanced markedly, with demonstrated efficacy in immune-mediated diseases such as psoriasis and psoriatic arthritis. This review provides a comprehensive overview of current knowledge of IL-17A, from its molecular characteristics to clinical applications. Full article

The gut–brain axis is increasingly implicated in Alzheimer’s disease (AD) pathogenesis, but the potential correlation between AD-associated gut microbiota and central inflammation remains largely unclear. This study aimed to explore their correlative link, with a focus on changes and involvement of Th17 cell-related factors in the gut–brain axis. Healthy C57BL/6J mice were pretreated with antibiotics for 1 week to deplete the indigenous gut microbiota, followed by 2 weeks of fecal microbiota transplantation (FMT) using feces from APP/PS1 AD model mice. Hematoxylin–eosin (H&E) staining, ELISA, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), 16S rDNA sequencing, and correlation analysis were performed to evaluate ileal and central pathological changes, Th17 cell-related inflammatory mediators, ileal microbiota composition, and their potential correlations. The results demonstrated that AD-FMT significantly induced ileal inflammatory infiltration and central inflammation in recipient mice, which was accompanied by abnormal expression of Th17 cell-related indicators, elevated levels of Th17-associated inflammatory factors, upregulated RORγt mRNA expression, and perturbed ileal microbiota composition. Correlation analysis further suggested that specific ileal bacterial taxa were closely correlated with Th17 cell-related inflammatory factors. These findings suggest a potential correlation between AD-associated microbiota and central inflammation, possibly by regulating intestinal Th17 cell-related indicators and altering gut microbial composition. This study provides correlative evidence supporting the involvement of the gut–brain axis in AD-related pathogenesis, highlighting the link between gut microbiota, central inflammation and Th17-related factors. Full article

Food allergies are rising globally, posing a multifactorial public health challenge driven by complex interactions among diet, immune development, and environmental exposures. This review highlights emerging insights into the cellular and molecular mechanisms by which specific dietary components, particularly vitamin A, fibre, indole compounds, and proteins, promote intestinal homeostasis. These nutrients act through both microbiota-dependent and -independent pathways, primarily in the small intestine, enhancing epithelial barrier integrity and supporting tolerogenic immune responses. Two key signalling axes, mediated by retinoic acid (RA) and aryl hydrocarbon receptor (AhR) ligands, converge to regulate RORγt-expressing immune cells, including group 3 innate lymphoid cells, TCRγδ⁺CD8αα⁺ intraepithelial lymphocytes (IELs), and Th17 cells, which are essential for secondary lymphoid organ development and barrier reinforcement. RA and AhR also guide the homing and specialization of diverse regulatory T cell subsets and CD4⁺ IELs, which collectively sustain peripheral tolerance to dietary antigens. Recent findings implicate RORγt⁺ antigen-presenting cells in the induction of peripheral Tregs during early life, particularly at weaning, underscoring a critical window for tolerance establishment. Microbial metabolites and commensal-derived signals further shape these immune pathways, reflecting the intricate interplay between host, diet, and microbiota in the regulation of oral tolerance. Full article

Teleost fish are the first evolutionary group to exhibit an innate and adaptive immune system. Within the mechanisms of adaptive immunity, fish possess, among others, T-helper cells (CD4-like) and their differentiation machinery, regulated by the master transcription factors T-bet, GATA3, Foxp3, and RORγ. Many studies support the existence of a non-neuronal cholinergic system involved in the immune response, named after the ability of leukocytes to synthesize de novo acetylcholine (ACh). Organophosphorus pesticides (OPs), such as diazoxon (DXN), are examples of compounds that act as cholinergic disruptors with immunotoxic effects. The present study aimed to evaluate the expression of transcription factors in leukocytes (spleen mononuclear cells, SMNCs) of Nile tilapia by modulating cholinergic pathways in immune cells using agonists, antagonists, and diazoxon (DXN), an anticholinesterase substance. The obtained data showed a significant increase in RORγ mRNA expression upon stimulation with the nicotinic agonist, whereas activation of the muscarinic receptor with its agonist increased T-bet mRNA expression. An alteration in RORγ expression levels induced by DXN exposure was also observed. The results suggest a probable directing of the immune response towards a pro-inflammatory profile orchestrated mainly by RORγ and T-bet transcription factors in response to cholinergic stimuli. Full article

Maternal immune activation (MIA) during pregnancy has been associated with increased risk of fetal loss and neurodevelopmental disorders in offspring. This review summarizes recent findings on the effects of MIA on fetal survival and microglial phenotype. Studies using polyinosinic–polycytidylic acid [poly(I:C)-induced MIA mouse models have revealed the crucial role of interleukin-17A (IL-17A) in mediating these effects. Overexpression of RORγt, a key transcription factor for IL-17A production, enhances poly(I: C)-induced fetal loss, possibly due to increased placental vulnerability. Intraventricular administration of IL-17A in fetal brains activates microglia and alters their localization, particularly in periventricular regions and the medial cortex. These activated microglia may contribute to abnormal synaptic pruning and excessive phagocytosis of neural progenitor cells, potentially leading to long-term neurodevelopmental abnormalities. The insights gained from MIA research have important clinical implications, including the potential for early identification of high-risk pregnancies and the development of novel preventive and therapeutic strategies. Future research should focus on elucidating the roles of other cytokines, determining critical periods of MIA susceptibility, and translating findings to human populations, while carefully considering ethical implications and the need for appropriate risk communication. Full article

Nuclear receptors (NRs) are transcription factors regulated by ligands that direct metabolism, development, and immunity. The NR superfamily constitutes a principal category of pharmacological targets for human ailments. Retinoic acid receptor-related orphan receptors (RORs) α, β, and γ are part of the nuclear receptor superfamily. They are nevertheless classified as “orphan” receptors due to the contentious nature of identifying their endogenous ligands. RORγ nuclear receptor protein further consists of two isoforms, namely RORγ1 and RORγ2 or RORγt. RORγt is largely found in immune cells and has been primarily associated with chronic inflammatory conditions. The expression of STAT3 is a major driver of Th17 differentiation and induces RORγt expression through the JAK-STAT pathway. Type 3 innate lymphoid cells (ILC3s), Th17 cells, and γδT cells express RORγt, the master transcription regulator for the pro-inflammatory cytokine interleukin IL-17. In chronic inflammatory skin disorders, a significant increase in IL-17 has been observed, which plays a key role in both immune cell recruitment to the site of inflammation and the propagation of tissue damage. In this review, we will discuss how RORγt regulates IL-17-driven inflammation and explore potential strategies to target the RORγt-IL-17 axis as a viable therapeutic intervention in chronic inflammatory skin disorders. Full article

Background and Objectives: Neuronal nitric oxide synthase (nNOS) overexpressed in melanoma plays a critical role in disease progression. Our previous studies demonstrated that nNOS inhibitors exhibited potent anti-melanoma activity and regulated PD-L1 expressions in the presence of interferon-gamma (IFN-γ). However, the role of nNOS in the melanoma immune response has not been well defined. Methods: Changes in gene expression profiles after nNOS inhibitor treatment were determined by transcriptomic analysis. A melanoma mouse model was used to determine the effects of nNOS inhibition on peripheral T cells and the in vivo anti-tumor activity of combining nNOS inhibitors with immune checkpoint blockade. Changes in human T cell activation through interleukin-2 (IL-2) production were investigated using an ex vivo co-culture system with human melanoma cells. Results: Cellular RNA analysis revealed significant changes in the genes involved in key signaling pathways after nNOS inhibitor HH044 treatment. Immunophenotyping of mouse peripheral blood mononuclear cells (PBMCs) after prolonged HH044 treatment showed marked increases in CD4⁺ and CD8⁺PD-1⁺ T cells. Ex vivo studies demonstrated that co-culturing human PBMCs with melanoma cells inhibited T cell activation, decreasing IL-2-secreting T cells both in the presence and absence of IFN-γ. PBMCs from a significant portion of donors (7/11, 64%), however, were reactivated by nNOS inhibitor pretreatment, displaying a significant increase in IL-2⁺ T cells. Distinctive T cell characteristics were noted at baseline among the responders with increased CD4⁺RORγt⁺ and reduced CD4 naïve T cells. In vivo mouse studies demonstrated that nNOS inhibitors, when combined with PD-1 blockade, significantly reduced tumor growth more effectively than monotherapy. Additionally, the median survival was extended from 43 days in the control mice to 176.5 days in mice co-treated with HH044 and anti-PD-1. Conclusions: Targeting nNOS is a promising approach to enhancing the anti-melanoma activity of immune checkpoint inhibitors, not only interfering with melanoma biological activities but also regulating the tumor microenvironment, which subsequently affects T cell activation and tumor immune response. Full article

A close association between obesity and food allergies has been described, but from the perspective of T cell differentiation, controversial findings exist regarding the impact of high-fat diet (HFD) feeding on the development of food allergies. Our study aimed to explore the relationship between HFD-induced mild obesity and food allergy development in female BALB/c mice. Following 18 weeks of HFD feeding, experimental animals demonstrated a 10.92% body weight gain accompanied by a 32.45% elevation in total cholesterol levels and a 39.50% increase in low-density lipoprotein–cholesterol levels. Upon allergen challenge, control diet (COD)-fed mice developed obvious food allergy symptoms and hypothermia, which were slightly alleviated in HFD-fed mice. Flow cytometry revealed that splenocytes from HFD-fed mice exhibited a 102.32% increase in CD4⁺T-bet⁺ T (Th1) cell populations and a 38.69% elevation in CD4⁺RORγt⁺ T (Th17) cell populations compared to COD-fed allergic mice. These changes corresponded with a 28.41% reduction in the Th2/Th1 ratio and a 56.67% increase in the Th17/Treg ratio. Moreover, real-time quantitative PCR showed that HFD-fed allergic mice had higher expressions of Foxp3, Occludin1, and TJP1 in the intestine. Therefore, we concluded that HFD-induced mild obesity restored the Th2/Th1 and Th17/Treg balance, reinforced intestinal barrier function, and thereby did not increase allergy risk in female BALB/c mice. Full article

Th17 lymphocytes are a distinct subpopulation of T cells that are characterized by the production of interleukins IL-17, IL-21, IL-22, and IL-26, and high expression of RORγt. These cells play an important role in inflammation and autoimmune diseases. Recent studies using rodent and human models have also highlighted their promising properties as agents in cellular immunotherapy for cancer. However, much less is known about the properties of canine Th17 lymphocytes, despite the domestic dog being an important model used in comparative medicine. In this study, we developed methods of activation and differentiation of canine CD4⁺ T lymphocytes towards the Th17 phenotype. Additionally, we targeted the Wnt/β-catenin signaling pathway to modulate the efficiency of Th17 cells differentiation. CD4⁺ T cells were successfully activated with magnetic EpoxyBeads, and in combination with the appropriate programming medium, they acquired the Th17 phenotype. Furthermore, indomethacin, an inhibitor of the Wnt/β-catenin pathway, significantly increased the efficiency of differentiation, causing elevated production of IL-17 and changed T cell metabolism by promoting oxidative phosphorylation. The protocol elaborated in our study provides an efficient method of canine Th17 lymphocyte differentiation. Our findings also suggested that the modification of the Wnt/β-catenin signaling pathway could be a valuable strategy for optimizing canine Th17 cell differentiation and advancing cell-based immunotherapy. Full article

Deficiencies in immune function increase susceptibility to infections and chronic diseases by impairing immune surveillance and tolerance mechanisms, especially in children with immature immune systems. Chronic inflammation associated with immune dysfunction can impair childhood by suppressing the GH–IGF-1. HT042 is composed of Astragalus mongholicus, Eleutherococcus senticosus, and Phlomis umbrosa, which are medicinal herbs that are traditionally utilized in East Asia to promote growth and enhance immune function; thus, HT042 itself holds potential as an immunomodulator. We evaluated the immunomodulatory effects of HT042 in a cyclophosphamide (CYP)-induced immunosuppressed mouse model, as well as in ex vivo primary splenocytes and RAW 264.7 macrophages. HT042 demonstrated remarkable immune-enhancing effects, including the restoration of weight loss and hematological parameters, as well as enhancing NK cell activity. Primary splenocytes treated with HT042 showed increased expression of CD3, CD4, and CD8, along with Th subset transcription factors (T-bet, GATA3, RORγt, Foxp3) and corresponding cytokines (IFN-γ, IL-4, IL-17, IL-10). In RAW 264.7 macrophages, HT042 increased nitric oxide production and upregulated NOS2, COX-2, and inflammatory cytokines (IL-6, IL-1β, TNF-α). It is noteworthy that HT042 enhances both innate and adaptive immune pathways, particularly via T cell modulation and macrophage activation, as this study is among the first to demonstrate such effects in the context of CYP-induced immunosuppression. Full article

The current definition of a postbiotic is a “preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”. Postbiotics can be mainly classified as metabolites, derived from intestinal bacterial fermentation, or structural components, as intrinsic constituents of the microbial cell. Secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) are bacterial metabolites generated by the enzymatic modifications of primary bile acids by microbial enzymes. Secondary bile acids function as receptor ligands modulating the activity of a family of bile-acid-regulated receptors (BARRs), including GPBAR1, Vitamin D (VDR) receptor and RORγT expressed by various cell types within the entire human body. Secondary bile acids integrate the definition of postbiotics, exerting potential beneficial effects on human health given their ability to regulate multiple biological processes such as glucose metabolism, energy expenditure and inflammation/immunity. Although there is evidence that bile acids might be harmful to the intestine, most of this evidence does not account for intestinal dysbiosis. This review examines this novel conceptual framework of secondary bile acids as postbiotics and how these mediators participate in maintaining host health. Full article

The uterine decidua contains NK cells differing in their characteristics from classical NK cells, as well as other populations of innate lymphoid cells (ILCs). ILC differentiation depends on the active transcription factors: ILC1 is characterized by T-bet expression, ILC2 is defined by RORα and GATA3, ILC3 expresses RORγt and AhR. We analyzed in vitro the expression of transcription factors by NK cells in the presence of trophoblast cells and cytokines and changes in NK cell cytotoxic activity. We used NK-92 and JEG-3 cell lines, which we cocultured in the presence of IFNγ, IL-10, IL-15, and TGFβ. Then, cells were treated with antibodies to AhR, Eomes, GATA-3, RORα, RORγt, and T-bet and were analyzed. We determined NK cell cytotoxicity towards K562 cells. To characterize the functional state of trophoblast cells, we estimated their secretion of TGFβ and βhCG. We showed that in the presence of trophoblasts, the expression of the classical NK cell transcription factors—Eomes, T-bet, as well as RORα, regulating ILC2 differentiation, and AhR, participating in NCR+ ILC3 formation—decreased in NK cells. RORγt expression typical for NCR- ILC3 remained unchanged. IFNγ inhibited AhR expression. IL-10 stimulated an increase in the number of T-bet+ ILC1-like cells. Both IL-10 and IFNγ suppressed RORα expression by NK cells and stimulated TGFβ secretion by trophoblasts. After coculture with trophoblast cells, NK cells reduced their cytotoxicity. These results indicated trophoblast cell influence on the acquisition of ILC1 and ILC3 characteristics by NK cells. Full article