Fish are exposed to numerous stressors which negatively affect their immune response and increase infection susceptibility. The risk of bacterial infections results in the excessive and preventive use of antibiotics. Therefore, we aimed to study how antibiotic treatment and restraint stress will affect the stress response, microbiota composition, gut morphology, and inflammatory reaction in common carp. Both restraint stress and antibiotic treatment increased cortisol level. Moreover, antibiotics induced dysbiosis in fish gut, manifested by a decrease in the total abundance of bacteria, and a shift in bacteria diversity, including a reduced number of Aeromonas, Bacteroides, Barnesiellaceae, Cetobacterium and Shewanella and an increased abundance of Flavobacterium. To a lesser extent, stress modified gut microbiota, as it decreased bacteria number and slightly changed the microbiota composition by decreasing Cetobacterium abundance and increasing Vibrio abundance. Microbiota of the antibiotic-treated and stressed fish shifted from the beneficial bacterial genera - Cetobacterium and Bacteroides, to the increased presence of unfavorable bacteria such as Brevinema, Flavobacterium and Desulfovibrionaceae. Stress and antibiotic-induced changes in the gut microbiota were related to the changes in the gut morphology when the higher abundance of goblet and rodlet cells and increased secretion activity of goblet cells were observed. Moreover, up-regulation of the expression of genes encoding pro-inflammatory mediators and cytokines involved in the Th17 immune response was present in the gut of the antibiotic-treated and stressed fish. We conclude that in carp antibiotics and stress alter the abundance and composition of the microbiota and induce Th17-dependent inflammatory reaction in the gut. Moreover, our results strongly suggest the interplay of the stress axis and the brain-gut-microbiota axis.

Psoriasis is one of the most common chronic inflammatory skin diseases. Many studies suggest that dendritic cells (DCs) and the T cell-mediated interleukin (IL)-23/IL-17 axis play a central role in the signaling pathway in the pathogenesis of psoriasis. Chlorella, also known as Parachlorella beijerinckii (PB), is a unicellular green alga that has long been used as a health food. It contains carotenoids that have antioxidant and anti-inflammatory effects. In this study, we investigated whether PB-derived carotenoids (PBCs) ameliorated inflammatory processes in an imiquimod (IMQ)-induced psoriasis-like mouse model and bone marrow-derived dendritic cells (BMDCs). We found that PBCs attenuated erythema, thickness, scaling, and neutrophil infiltration in the skin tissue of the IMQ-induced psoriasis-like mice. Moreover, PBCs suppressed psoriasis-related pro-inflammatory cytokine expression, DC activation, and IL-17A production by γδ T cells in IMQ-induced psoriasis-like mice. In IMQ-induced BMDCs, PBCs suppressed the expression levels of pro-inflammatory cytokines, including IL-23; IL-1β; and IL-6; and CD40/CD86, a marker of DC activation. Additionally, PBCs inhibited the nuclear factor kappa B, p38, and c-Jun NH2-terminal kinase inflammatory signaling pathways and the mitochondrial reactive oxygen species (mitoROS)-triggered inflammasome activation pathway. PBCs also activated the extracellular regulated protein kinase/NF-E2-related factor-2 (ERK/Nrf2) pathway in BMDCs. Moreover, PBCs suppressed the harmful effects of pro-inflammatory cytokine gene expression and mitoROS and inflammasome activation via ERK/Nrf2 pathway activation in IMQ-induced BMDCs. In conclusion, PBCs may be beneficial in the management of psoriatic inflammation.

Inflammation can generate pathogenic Th17 cells and cause an inflammatory dysbiosis. In the context of inflammatory bowel disease (IBD), these inflammatory Th17 cells and dysbiotic microbiota may perpetuate injury to intestinal epithelial cells. However, many models of IBD like T-cell transfer colitis and IL-10-/- mice rely on the absence of regulatory pathways, so it is difficult to tell if inflammation can also induce protective Th17 cells.

We subjected C57BL6, RAG1-/-, or JH-/- mice to systemic or gastrointestinal (GI) Citrobacter rodentium (Cr). Mice were then subjected to 2.5% dextran sodium sulfate (DSS) to cause epithelial injury. Fecal microbiota transfer was performed by bedding transfer and co-housing. Flow cytometry, qPCR, and histology were used to assess mucosal and systemic immune responses, cytokines, and tissue inflammation. 16s sequencing was used to assess gut bacterial taxonomy.

Transient inflammation with GI but not systemic Cr was protective against subsequent intestinal injury. This was replicated with sequential DSS collectively indicating that transient inflammation provides tissue-specific protection. Inflammatory Th17 cells that have a tissue-resident memory (TRM) signature expanded in the intestine. Experiments with reconstituted RAG1-/-, JH-/- mice, and cell trafficking inhibitors showed that inflammation-induced Th17 cells were required for protection. Fecal microbiota transfer showed that the inflammation-trained microbiota was necessary for protection, likely by maintaining protective Th17 cells in situ.

Inflammation can generate protective Th17 cells that synergize with the inflammation-trained microbiota to provide host resiliency against subsequent injury, indicating that inflammation-induced Th17 TRM T cells are heterogenous and contain protective subsets.

Th17 cells can perform either regulatory or inflammatory functions depending on the cytokine microenvironment. These plastic cells can transdifferentiate into Tregs during inflammation resolution, in allogenic heart transplantation models, or in cancer through mechanisms that remain poorly understood. Here, we demonstrated that NLRP3 expression in Th17 cells is essential for maintaining their immunosuppressive functions through an inflammasome-independent mechanism. In the absence of NLRP3, Th17 cells produce more inflammatory cytokines (IFNγ, Granzyme B, TNFα) and exhibit reduced immunosuppressive activity toward CD8+ cells. Moreover, the capacity of NLRP3-deficient Th17 cells to transdifferentiate into Treg-like cells is lost. Mechanistically, NLRP3 in Th17 cells interacts with the TGF-β receptor, enabling SMAD3 phosphorylation and thereby facilitating the acquisition of immunosuppressive functions. Consequently, the absence of NLRP3 expression in Th17 cells from tumor-bearing mice enhances CD8 + T-cell effectiveness, ultimately inhibiting tumor growth.

The etiology of acute myeloid leukemia (AML) is complex, including genetic and environmental abnormalities. The immune system anomalies play an essential role in the process of leukemogenesis. However, the immunopathological factors, including abnormal T helper (Th) subsets, contributing to the initiation and progression of this neoplasm, require further investigation. Considering the previously mentioned data, we decided to study the expression pattern of transcription factors T-bet, Foxp3, and RORγt that regulate Th1, Treg, and Th17, respectively, in acute myeloid leukemia with correlation to clinical and other investigation data and treatment outcomes. This study was conducted on 80 newly diagnosed patients with AML recruited from the National Cancer Institute, Cairo University, and 25 healthy control subjects. The AML patient cohort consisted of 30 females (37.5%) and 50 males (62.5%), ranging from 18 to 74 years old. The control group was 8 females (32%) and 17 males (68%), with ages ranging from 23 to 40 years old. Samples were provided from the bone marrow of donor cases for allogeneic bone marrow transplantation. The diagnosis of acute myeloid leukemia was based on morphologic and cytochemical evaluation, immunophenotyping, and complementary cytogenetics according to WHO criteria. Upshift from the normal T-bet intensity of power (MFI), RORγt+ CD4+ T lymphocyte frequency (%) with downshift from the normal FOXP3 intensity of power (MFI), may suggest a state of inflammation. In contrast, an upshift from the normal FOXP3+ CD4+ T lymphocyte frequency (%) may reflect a state of immunosuppression in the bone marrow microenvironment of AML. Combined, they constitute a sophisticated scenario of immunological disorder in AML. Co-expression of T-bet and RORγt transcription factors in CD4+ T lymphocytes in both normal and AML groups may suggest CD4+ T lymphocyte plasticity.

Excess dietary salt and salt-sensitivity contribute to cardiovascular disease. Distinct T cell phenotypic responses to high salt and hypertension, as well as influences from environmental cues, are not well understood. The aryl hydrocarbon receptor (AhR) is activated by dietary ligands, promoting T cell and systemic homeostasis. We hypothesized that activating AhR supports CD4+ homeostatic functions, such as cytokine production and mobilization, in response to high salt intake while mitigating salt-sensitive hypertension. In the intestinal mucosa, we demonstrate that a high-salt diet (HSD) is a key driving factor, independent of hypertension, in diminishing interleukin 17A (IL-17A) production by CD4+ T (Th17) cells without disrupting circulating cytokines associated with Th17 function. Previous studies suggest that hypertensive patients and individuals on a HSD are deficient in AhR ligands or agonistic metabolites. We found that activating AhR augments Th17 cells during experimental salt-sensitive hypertension. Further, we demonstrate that activating AhR in vitro contributes to sustaining Th17 cells in the setting of excess salt. Using photoconvertible Kikume Green-Red mice, we also revealed that HSD drives CD4+ T cell mobilization. Next, we found that excess salt augments T cell mobilization markers, validating HSD-driven T cell migration. Also, we found that activating AhR mitigates HSD-induced T cell migration markers. Using telemetry in a model of experimental salt-sensitivity, we found that activating AhR prevents the development of salt-sensitive hypertension. Collectively, stimulating AhR through dietary ligands facilitates immunologic and systemic functions amid excess salt intake and restrains the development of salt-sensitive hypertension.

Uveitis involves a complex interplay of immune cell infiltration and cytokine imbalances, with Th17 cells playing a central role in this process. Th17 cells contribute to disease pathogenesis by promoting inflammation, recruiting additional immune cells, and directly damaging retinal tissues. This review discusses the current knowledge on therapeutic strategies targeting Th17-related cytokines, including cytokine blockade, small molecule inhibitors, and immunomodulatory approaches. Traditionally, Th17-related cytokines have been viewed as pro-inflammatory agents in uveitis. However, emerging research has highlighted the capacity of the Th17 response to express immunoregulatory cytokines, notably IL-10, IL-24, and TGF-β. This suggest that the Th17 response may have a dualistic role that includes immune suppression. In this review, we will discuss this paradoxical nature of Th17 cells in immune regulation and inflammation that they can both promote and mitigate uveitis. We expected that a deeper understanding of these mechanisms is imperative for the innovation of novel therapeutics that could consider the dual role of Th17 response in the pathogenesis of uveitis. By finely tuning the Th17 response to preserve retinal integrity and function, these new treatments could bring significant benefits to patients with uveitis. This review aims to shed light on the complexities of the Th17 response in uveitis and its implications for future therapeutic strategies.

GPR171 suppresses T cell immune responses involved in antitumour immunity, while its role in inflammatory bowel disease (IBD) pathogenesis remains unclear.

We aimed to investigate the role of GPR171 in modulating CD4+ T cell effector functions in IBD and evaluate its therapeutic potential.

We analysed GPR171 expression in colon biopsies and peripheral blood samples from patients with IBD and assessed the impact of GPR171 on CD4+ T cell differentiation through administration of its endogenous ligand (BigLEN). We further determined the role of GPR171 in dextran sulfate sodium (DSS)-induced colitis and CD45RBhighCD4+ T-cell transfer colitis model and deciphered the underlying mechanisms using RNA sequencing (RNA-seq) and lipidomics. We developed a novel BigLEN-based Fc fusion protein (BigLEN-Fc) and evaluated its potential in preventing and treating colitis.

GPR171 was markedly increased in inflamed mucosa and CD4+ T cells of patients with IBD compared with controls. BigLEN-triggered GPR171 activation inhibited Th17 cell differentiation in vitro. GPR171 deficiency exacerbated DSS- and CD45RBhighCD4+ T cell-induced colitis in mice, characterised by increased Th17 cell responses in intestinal mucosa. Mechanistically, GPR171 deficiency promoted Th17 cell differentiation and altered lipidome profile in Th17 cells via the cAMP-pCREB-FABP5 axis. Blockage of FABP5 reduced Th17 cell differentiation in vitro and ameliorated DSS-induced colitis in Gpr171 -/- mice. Furthermore, BigLEN-mutFc administration potently mitigated colitis in mice.

GPR171 deficiency promotes Th17 cell differentiation and causes lipid metabolism perturbation, contributing to intestinal inflammation in a FABP5-dependent manner. Target therapy (eg, BigLEN-Fc) represents a novel therapeutic approach for IBD treatment.

It is well known that T-cell metabolism and function are intimately linked. Metabolic reprogramming is a dynamic process that provides the necessary energy and biosynthetic precursors while actively regulating the immune response of T cells. As such, aberrations and dysfunctions in metabolic (re)programming, resulting in altered metabolic endotypes, may have an impact on disease pathology in various contexts. With the increasing demand for personalized and highly specialized medicine and immunotherapy, understanding metabolic profiles and T-cell subset dependence on specific metabolites will be crucial to harness the therapeutic potential of immunometabolism and T cell bioenergetics. In this review, we dissect metabolic alterations in different T-cell subsets in autoimmune and viral inflammation, T cell and non-T-cell malignancies, highlighting potential anchor points for future treatment and therapeutic exploitation.

Autoimmune thyroid diseases (AITD), a group of prevalent and persistent immune-mediated disorders affecting the endocrine system, can progressively result in total thyroid failure, thereby drastically impacting metabolic processes. Given the inadequacies of current clinical approaches to managing AITD, The exigency to investigate novel therapeutic strategies demands immediate attention, given the limitations and potential resistances associated with conventional approaches. Si-Ni-San (SNS), first chronicled in the esteemed Eastern Han Dynasty medical text " Treatise on Cold Damage and Miscellaneous Diseases" circa 200-210 AD, is a time-honored remedy known for its harmonizing effects on the liver and invigorating properties for the spleen. Research indicates that saikosaponins and peony glycosides, two primary constituents of SNS, possess anti-inflammatory properties and can ameliorate immune dysfunction in the treatment of AITD. Despite initial insights, a comprehensive exploration of the underlying mechanisms by which SNS alleviates AITD symptoms requires further in-depth investigation to decipher their intricate interplay.

This study aimed to identify the key therapeutic components of SNS for the treatment of AITD and to elucidate the underlying molecular mechanisms, revealing potential targets.

We initially screened prospective components of SNS for AITD therapy through comprehensive database exploration, followed by an evaluation of the results via PPI networks. To illuminate the therapeutic mechanisms of SNS in AITD, we employed GO enrichment analysis and surveyed the KEGG pathways. Employing UHPLC-QE-MS, we conducted an in-depth analysis of SNS's principal elements, complemented by molecular docking studies to unravel their interaction dynamics. Finally, we substantiated the central therapeutic pathway of SNS in the treatment of AITD using an experimental autoimmune thyroiditis (EAT) mouse model, validated meticulously through in vivo experimentation.

Network pharmacology analysis revealed 32 common targets from the overlap between SNS and AITD-related targets. Based on subsequent PPI network and KEGG analysis, we focused on the IL-6/JAK2/STAT3/IL-17 pathway, which drives the differentiation of Th17 cells, as a central therapeutic target of SNS in AITD. Crucially, our in vivo findings, substantiated through immunohistochemical, Western blot, RT-qPCR analyses and Flow cytometry analysis, reveal SNS's therapeutic potential in AITD. It effectively dampens IL-6 production, inhibits IL-6/JAK2/STAT3/IL-17 pathway activation, and rebalances the Th17/Treg cell ratio, thus elucidating its anti-inflammatory mechanism.

The protective effect of SNS against AITD is likely mediated through the modulation of the IL-6/JAK2/STAT3/IL-17 pathway and the restoration of balance within the Th17/Treg ratio. This suggests that SNS may exert its therapeutic effects on AITD by targeting these key molecular mechanisms, thereby providing a novel perspective for the treatment of AITD.

The objective of this systematic review was to identify genetic variants of the IL-23, IL-17, IL-23R and IL-17R genes and isoforms and its possible association with increased development of periodontitis and peri-implantitis.

A systematic review was prepared according to the guidelines, registered in the OSF database with the registration number: 10.17605/OSF. IO/X95ZC. The electronic search was performed in four databases: PubMed, Scopus, Web of Science, and Google Scholar from 1984 until March 15th, 2024. The JBI Critical Appraisal Checklist for Case-Control Studies was used to assess the quality of included studies.

Eighteen papers with a case-control design were those that ultimately met the eligibility criteria. A total of 3904 individuals (2315 with periodontitis and 90 with peri-implantitis), and 1589 healthy subjects) were studied. The age range of the study population was 14-70 years, with a mean age ± (SD) of 40.43 ± 6.33 years. A total of 28 genetic variants corresponding to the IL-17A (rs 2275913, rs 3819024, rs 10484879) IL-17F (rs 763780), IL-17R (rs 879576) and IL-23R (rs 11209026) genes were analyzed in this study. Six (33.3%) studies found an association between the IL-17A 197 G/A (rs 2275913) genetic variant and peri-implantitis and periodontitis. One study (5.5%) found an association between the IL-17A rs10484879 variant and peri-implantitis and periodontitis.

Six polymorphisms were evaluated, highlighting rs 2275913 of the cytokine IL-17A in patients with periodontitis or peri-implantitis. Only 50% of studies found an association despite having a small sample. This suggests that other factors such as the degree of disease, systemic diseases and ethnic groups studied may play a role.

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As a common pathogen of rhinosinusitis, the role of Staphylococcus aureus in modulating autophagy through STING activation and Th17 cell differentiation in CRSwNP remains unexplored. This study aims to investigate how S. aureus regulates Th17 cell differentiation and the occurrence and development of autophagy in CRS by inducing STING expression.

Immunoblotting and flow cytometry were employed to assess the expression levels of STING, RORγt, LC3B, and MUC5AC, as well as Th17 markers in cells. HNECs were co-cultured with S. aureus in vitro to explore its regulatory effects.

STING expression was found to be decreased in CRSwNP tissues, while RORγt, LC3B, and MUC5AC levels were elevated. S. aureus was shown to induce Th17 differentiation via STING regulation. STING activators reduced Th17 inflammation, while autophagy activators increased autophagosomes and MUC5AC levels.

The STING system may play a protective role in the inflammatory response of nasal epithelial cells. S. aureus inhibits STING, not only by promoting the differentiation of pathogenic Th17 cells but also by increasing autophagy levels in nasal epithelial cells. Both mechanisms contribute to the enhanced expression of MUC5AC, facilitating the progression of CRSwNP.

Epidemiological studies link exposure to viral infection during pregnancy, including influenza A virus (IAV) infection, with increased incidence of neurodevelopmental disorders (NDDs) in offspring. Models of maternal immune activation (MIA) using viral mimetics demonstrate that activation of maternal intestinal T helper 17 (TH17) cells, which produce effector cytokine interleukin (IL)-17, leads to aberrant fetal brain development, such as neocortical malformations. Fetal microglia and border-associated macrophages (BAMs) also serve as potential cellular mediators of MIA-induced cortical abnormalities. However, neither the inflammation-induced TH17 cell pathway nor fetal brain-resident macrophages have been thoroughly examined in models of live viral infection during pregnancy. Here, we inoculated pregnant mice with two infectious doses of IAV and evaluated peak innate and adaptive immune responses in the dam and fetus. While respiratory IAV infection led to dose-dependent maternal colonic shortening and microbial dysregulation, there was no elevation in intestinal TH17 cells nor IL-17. Systemically, IAV resulted in consistent dose- and time-dependent increases in IL-6 and IFN-γ. Fetal cortical abnormalities and global changes in fetal brain transcripts were observable in the high-but not the moderate-dose IAV group. Profiling of fetal microglia and BAMs revealed dose- and time-dependent differences in the numbers of meningeal but not choroid plexus BAMs, while microglial numbers and proliferative capacity of Iba1+ cells remained constant. Fetal brain-resident macrophages increased phagocytic CD68 expression, also in a dose- and time-dependent fashion. Taken together, our findings indicate that certain features of MIA are conserved between mimetic and live virus models, while others are not. Overall, we provide consistent evidence of an infection severity threshold for downstream maternal inflammation and fetal cortical abnormalities, which recapitulates a key feature of the epidemiological data and further underscores the importance of using live pathogens in NDD modeling to better evaluate the complete immune response and to improve translation to the clinic.

Lipid mediator, palmitoylethanolamide (PEA) has recently attracted attention as a potential therapeutic option for various inflammatory autoimmune diseases. It has been reported that PEA exerts an inhibitory effect on inflammation triggered by PRRs, particularly Toll-like receptors expressed on myeloid antigen-presenting cells. However, the precise role of PEA in T cell development and function has not yet been elucidated. Here, we found that PEA suppressed the differentiation of Type 1 T helper (Th1) cells and Th17 cells, which are known to cause autoimmune diseases, as well as Th2 cells, which are associated with allergic diseases. This suppression occurs by inhibiting the expression of the master transcription factors crucial for their differentiation in vitro. Notably, PEA had no impact on the process of differentiating regulatory T cells, which play a crucial role in preventing the onset of autoimmune diseases. To further confirm the effect of PEA in vivo, we administered PEA to a Toxoplasma gondii infection model and an ovalbumin-induced allergic rhinitis model. Mice infected with T. gondii, in which Th1 responses are important for pathogen eradication, exhibited enhanced susceptibility. Mice with allergic rhinitis, where Th2 responses contribute to an exacerbation of symptoms, showed alleviated symptoms. Collectively, these findings suggest that PEA has potential applications as a new therapeutic agent for inflammatory autoimmune and allergic diseases based on excessive T cell activity.

Regulatory T cells (Tregs) are immune regulatory T cells that are vital for controlling inflammation. The role of Tregs in inflammatory diseases namely psoriatic arthritis (PsA) is still poorly understood. The underlying reason being a lack of robust unbiased analysis to test the immune regulatory phenotype of human Tregs. Here, we propose that checkpoint receptors can identify functional Tregs in PsA. Using unbiased BD Rhapsody single-cell analysis, we have analyzed the expression pattern of checkpoint receptors in Tregs and found that PsA Tregs are enriched in the expression of CTLA4, TIGIT, PD-1, and GITR while TIM3 was downregulated. Furthermore, PD-1+ Tregs in PsA had an increased type 1 phenotype and expressed the protease asparaginyl endopeptidase. By harnessing the PD-1 signaling pathway and inhibiting asparaginyl endopeptidase, PsA Treg function was significantly enhanced in in vitro suppressor assays. Next, we interrogated the cell interaction pathways of Tregs in PsA and found a diminished crosstalk with circulating osteoclast precursors through the CD244-CD48 coreceptor pathways. Therapeutically, PsA Treg function could be enhanced by modulating PD-1 and osteoclast interactions. Our study suggests that unconventional immune cell crosstalk with Tregs is severely diminished in PsA.

T-helper 17 cells play a dual role in immunological responses, serving as essential components in tissue homeostasis and host defense against microbial pathogens while also contributing to proinflammatory conditions and autoimmunity. While transforming growth factor β1 is pivotal for the differentiation of nonpathogenic T-helper 17 cells, the role of transforming growth factor β3 and activin in steering T-helper 17 cells toward a pathogenic phenotype has been acknowledged. However, the molecular mechanisms governing this dichotomy remain elusive. In this study, we demonstrate that the transcription factor Foxo1 is upregulated in a transforming growth factor β1 dose-dependent manner, serving as a critical regulator that specifically modulates the fate of pathogenic T-helper 17 cells. Analyses in both patients with uveitis and an experimental autoimmune uveitis mouse model reveal a strong correlation between disease severity and diminished Foxo1 expression levels. Ectopic expression of Foxo1 selectively attenuates T-helper 17A production under pathogenic T-helper 17-inducing conditions. Moreover, enhanced Foxo1 expression, triggered by transforming growth factor β1 signaling, is implicated in fatty acid metabolism pathways that favor nonpathogenic T-helper 17 differentiation. Our drug screening identifies several US Food and Drug Administration-approved compounds can upregulate Foxo1. Collectively, our findings offer evidence that Foxo1 serves as a molecular switch to specifically control pathogenic vs nonpathogenic T-helper 17 differentiation in a transforming growth factor β1-dependent manner. Targeting Foxo1 could be a promising therapeutic strategy for autoimmune diseases.

The neurological deficits following traumatic spinal cord injury are associated with severe patient disability and economic consequences. Currently, an increasing number of studies are focusing on the importance of ferroptosis during acute organ injuries. However, the spatial and temporal distribution patterns of ferroptosis during SCI and the details of its role are largely unknown. In this study, in vivo experiments revealed that microglia are in close proximity to macrophages, the major cell type that undergoes ferroptosis following SCI. Furthermore, we found that ferroptotic macrophages aggravate SCI by inducing the proinflammatory properties of microglia. In vitro studies further revealed ferroptotic macrophages increased the expression of IL-1β, IL-6, and IL-23 in microglia. Mechanistically, due to the activation of the NF-κB signaling pathway, the expression of IL-1β and IL-6 was increased. In addition, we established that increased levels of oxidative phosphorylation cause mitochondrial reactive oxygen species generation and unfolded protein response activation and trigger an inflammatory response marked by an increase in IL-23 production. Our findings identified that targeting ferroptosis and IL-23 could be an effective strategy for promoting neurological recovery after SCI.

Cordyceps polysaccharide (CSP) has been shown to exhibit anti-inflammatory and antioxidant effects, with potential applications in ischemic stroke. This work is to explore the interventional potential of CSP in MCAO rats and the effects on the intestinal and cerebral IL-23/IL-17 axis. We conducted pharmacological experiments and mechanism exploration in MCAO rats. Our research showed that CSP improved the neurological function and cerebral pathological morphology, reduced cerebral infarction volume and water content in MCAO rats. We also found that CSP significantly decreased the IL-1β, TNF-α and IL-6 in the ischemic brain and enhanced the ability of MCAO rats to resist oxidative stress. Additionally, CSP improved intestinal barrier, inhibited the activation of the TLR4/Myd88/NF-κβ signaling pathway and IL-23/IL-17 axis. The study results demonstrated the effectiveness of CSP in interfering with MCAO rats. The mechanism appears to be related to protecting the intestinal barrier and inhibiting the IL-23/IL-17 axis.

This work aims to investigate whether RIP2 silencing in naive CD4+ T cells from lupus-prone mice impacts Th17 cell activity or differentiation in vitro.

Naive CD4+ T cells isolation from MRL/lpr mice's spleens. Three RNA interference target sequences of RIP2 were packaged with lentivirus and transfected into naive CD4+ T cells. The shRIP2 with the highest interference efficiency was selected and transfected into naive CD4+ T cells. Naive CD4+ T cells were cultured under conventional (TGF-β1 and IL-6) and pathogenic (IL-6, IL-23, IL-1β) differentiation environments, respectively. Then, RT-qPCR, Western blot or Flow Cytometry were used for measuring the amounts of RIP2 and IL-17 and the differentiation of Th17 cells in two settings.

Under the conventional Th17 (cTh17) cell differentiation environment (TGF-β1 and IL-6), RIP2 deficiency is linked to decreased IL-17A levels (1.00 ± 0.03 vs 0.80 ± 0.03) and attenuated cTh17 cell (2.46 ± 0.08 vs 0.78 ± 0.03) differentiation (all, P < 0.05). Under the pathogenic Th17 (pTh17) cell environment (IL-1β, IL-23, IL-6), RIP2 deficiency is linked to elevated IL-17A levels (1.03 ± 0.05 vs 1.63 ± 0.07) and enhanced pTh17 cell (3.69 ± 0.19 vs 5.49 ± 0.10) differentiation (all, P < 0.05).

Our data suggest that RIP2 inhibition induces preferential differentiation of naive CD4+ T cells to pathogenic Th17 cells, while being able to upregulate IL-17A levels in the context of pTh17 cell differentiation. Our study opens up new research areas to reveal the underlying mechanisms and potential therapeutic targets for the prevention and treatment of SLE patients. Key Points • Silencing of RIP2 in naive CD4+ T cells from lupus-prone mice promotes pathogenic Th17 (pTh17) cell differentiation and IL-17A production under pTh17 cell (IL-1β, IL-23, and IL-6) conditions. • RIP2 deficiency in naive CD4+ T cells reduces conventional Th17 (cTh17) cell differentiation and IL-17A production under cTh17 cell (TGF-β1 and IL-6) conditions. • RIP2-deficient naive CD4+ T cells preferentially differentiate towards pTh17 cells rather than cTh17 cells in vitro. • Inhibition of RIP2 may be involved in the development of SLE via effects on Th17/IL-17.

Acute lung injury (ALI) is primarily driven by an intense inflammation in the alveolar epithelium. Key to this is the pro-inflammatory cytokine, Interleukin 17 (IL-17), which influences pulmonary immunity and modifies p53 function. The direct role of IL-17A in p53-fibrinolytic system is still unclear, it is important to evaluate this mechanism to regulate the ALI progression to idiopathic pulmonary fibrosis (IPF). C57BL/6 mice, exposed to recombinant IL-17A protein and treated with curcumin, provided insight into IL-17A mechanisms and curcumin's potential for modulating early pulmonary fibrosis stages. A diverse methodology, including proteomics, single-cell RNA sequencing (scRNA-seq) integration, molecular, and Schroedinger approach were utilized. In silico approaches facilitated the potential interactions between curcumin, IL-17A, and apoptosis-related proteins. A notable surge in the expression levels of IL-17A, p53, and fibrinolytic components such as Plasminogen Activator Inhibitor-1 (PAI-I) was discerned upon the IL17A exposure in mouse lungs. Furthermore, the enrichment of pathways and differential expression of proteins underscored the significance of IL-17A in governing downstream regulatory pathways such as inflammation, NF-kappaB signaling, Mitogen-Activated Protein Kinases (MAPK), p53, oxidative phosphorylation, JAK-STAT, and apoptosis. The integration of scRNA-seq data from 20 IPF and 10 control lung specimens emphasized the importance of IL-17A mediated downstream regulation in PF patients. A potent immuno-pharmacotherapeutic agent, curcumin, demonstrated a substantial capacity to modulate the lung pathology and molecular changes induced by IL-17A in mouse lungs. Human IPF single cell data integration confirmed the effects of IL-17A mediated fibrinolytic components in ALI to IPF progression.

Angiotensin-converting enzyme 2 receptors (ACE2R) are requisite to enter the host cells for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). ACE2R is constitutive and functions as a type I transmembrane metallo-carboxypeptidase in the renin-angiotensin system (RAS). On thyroid follicular cells, ACE2R allows SARS-CoV-2 to invade the thyroid gland, impose cytopathic effects and produce endocrine abnormalities, including stiff back, neck pain, muscle ache, lethargy, and enlarged, inflamed thyroid gland in COVID-19 patients. Further damage is perpetuated by the sudden bursts of pro-inflammatory cytokines, which is suggestive of a life-threatening syndrome known as a "cytokine storm". IL-1β, IL-6, IFN-γ, and TNF-α are identified as the key orchestrators of the cytokine storm. These inflammatory mediators upregulate transcriptional turnover of nuclear factor-kappa B (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and mitogen-activated protein kinase (MAPK), paving the pathway for cytokine storm-induced thyroid dysfunctions including euthyroid sick syndrome, autoimmune thyroid diseases, and thyrotoxicosis in COVID-19 patients. Targeted therapies with corticosteroids (dexamethasone), JAK inhibitor (baricitinib), nucleotide analogue (remdesivir) and N-acetyl-cysteine have demonstrated effectiveness in terms of attenuating the severity and frequency of cytokine storm-induced thyroid dysfunctions, morbidity and mortality in severe COVID-19 patients. Here, we review the pathogenesis of cytokine storms and the mechanisms and pathways that establish the connection between thyroid disorder and COVID-19. Moreover, cross-talk interactions of signalling pathways and therapeutic strategies to address COVID-19-associated thyroid diseases are also discussed herein.

Immunotherapy targeting the autoimmune process in type 1 diabetes (T1D) can delay the loss of β-cells but needs to have minimal adverse effects to be an adjunct to insulin in the management of T1D. Ustekinumab binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, targeting development of T helper 1 cells and T helper 17 cells (TH1 and TH17 cells) implicated in the pathogenesis of T1D. We conducted a double-blind, randomized controlled trial of ustekinumab in 72 adolescents aged 12-18 years with recent-onset T1D. Treatment was well tolerated with no increase in adverse events. At 12 months, β-cell function, measured by stimulated C-peptide, was 49% higher in the intervention group (P = 0.02), meeting the prespecified primary outcome. Preservation of C-peptide correlated with the reduction of T helper cells co-secreting IL-17A and interferon-γ (TH17.1 cells, P = 0.04) and, in particular, with the reduction in a subset of TH17.1 cells co-expressing IL-2 and granulocyte-macrophage colony-stimulating factor (IL-2+ GM-CSF+ TH17.1 cells, P = 0.04). A significant fall in β-cell-targeted (proinsulin-specific) IL-17A-secreting T cells was also seen (P = 0.0003). Although exploratory, our data suggest a role for an activated subset of TH17.1 cells in T1D that can be targeted with minimal adverse effects to reduce C-peptide loss, which requires confirmation in a larger study. (International Standard Randomised Controlled Trial Number Registry: ISRCTN 14274380).

QingChang-XiaoPi Decoction (QCXPY), a Chinese herbal prescription, has been employed in the treatment of ulcerative colitis (UC) in China. However, its molecular mechanism of action in UC remains unclear.

To elucidate the therapeutic effects of QCXPY against UC and reveal its mechanism of action.

We conducted a single-arm observation to evaluate the clinical efficacy of QCXPY in patients with mild-to-moderate UC. Inclusion and exclusion criteria were established to ensure the eligibility of participants, with a focus on excluding patients with specific conditions or complications that could confound the results.

The expression of inflammatory factors in patients' serum was detected using a Luminex assay. The main components of QCXPY were identified using UHPLC-Q-TOF-MS. Network pharmacology was employed to predict potential therapeutic targets and their mechanisms of action. The efficacy of QCXPY was evaluated using a dextran sulfate sodium (DSS)-induced mouse model. Disease activity index (DAI), histopathological score, cytokine detection by ELISA, T-helper 17 (Th17) cell proportion by flow cytometry, expression of the IL-23/IL-17 axis, and changes in the levels of its downstream effectors were detected by immunohistochemistry, immunofluorescence, and western blotting.

QCXPY could alleviate the symptoms of diarrhea, abdominal pain, abdominal distension, and purulent stool in patients with mild-to-moderate UC. Moreover, it reduced the expression of IL-6, IL-17, and IL-23 in serum; alleviated DSS-induced experimental colitis in mice; reduced DAI, pathological scores, and the expressions of IL-6, IL-17, and IL-23 in colon tissue; and decreased the proportion of pathogenic Th17 cells and the expression of STAT3 and phospho-STAT3.

This study confirmed for the first time that QCXPY could alleviate intestinal symptoms, reduce the levels of serum inflammatory factors, and improve the quality of life of patients with mild-to-moderate UC. Its mechanism of action may involve reducing the secretion of inflammatory cytokines, moderating the pathogenicity of Th17 cells, and inhibiting STAT3 phosphorylation, thereby alleviating intestinal inflammation in UC.

This perspective article delves into a novel integration of Yin-Yang theory-an ancient Chinese philosophical cornerstone-with the sophisticated realm of immunology. Given the intricate concepts inherent in immunology, many students find it challenging to comprehend the delicate mechanisms governing immune equilibrium and regulation. Given the deep-rooted understanding of Yin-Yang theory among Chinese students, we advocate for an educational strategy that contextualizes the concept of immune equilibrium within the framework of Yin-Yang, thereby offering a more intuitive and engaging learning experience. This method not only capitalizes on the cultural significance of Yin-Yang, but also corresponds to its principles of equilibrium and harmony, thus mirroring the homeostatic essence of immune responses. This article critically assesses this technique's capacity to bolster immune comprehension amongst Chinese students, while also considering its limitations. Despite these limitations, the fusion of these seemingly divergent fields holds substantial promise for augmenting immunology education, promoting critical thinking, and advancing cross-cultural academic discourse. The amalgamation of age-old philosophical insights with modern scientific exploration prompts a reassessment of educational methodologies within immunology, underscoring a novel pedagogical approach that bridges traditional wisdom with contemporary scientific education.

The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C. rodentium infection induced increased ROS and disrupted mitochondrial function and TFAM-driven mitochondrial gene expression, resulting in decreased cellular ATP. These changes impaired the PI3K/AKT/mTOR pathway, reducing phosphorylation of 4E-BP1 and consequently limiting IL-22 translation. The resultant low IL-22 levels led to poor bacterial clearance, severe intestinal damage, and high mortality. Our findings highlight a previously unrecognized, essential role of Th17 cell-intrinsic GSH in promoting mitochondrial function and cellular signaling for IL-22 protein synthesis, which is critical for intestinal integrity and defense against gastrointestinal infections.

Atherosclerotic cardiovascular disease (ASCVD) is the most important cause of morbidity and mortality worldwide. While it is traditionally attributed to lipid accumulation in the vascular endothelium, recent research has shown that plaque inflammation is an important additional driver of atherogenesis. Though clinical outcome trials utilizing anti-inflammatory agents have proven promising in terms of reducing ASCVD risk, it is imperative to identify novel actionable targets that are more specific to atherosclerosis to mitigate adverse effects associated with systemic immune suppression. To that end, this review explores the contributions of various immune cells from the innate and adaptive immune system in promoting and mitigating atherosclerosis by integrating findings from experimental studies, high-throughput multi-omics technologies, and epidemiological research.

Autoimmune Thyroiditis (AIT) is the most common thyroid disease; however, there were no measures to prevent the progression of the disease. The present study attempts to identify that Notch signaling regulates the differentiation of T helper 17 (Th17) cells by activating downstream Phosphatidylinositol-3 kinase/protein kinase/mechanistic target of rapamycin complex 1 (PI3K/AKT/mTORC1) pathway participating in the thyroid injury of the experimental autoimmune thyroiditis (EAT).

In vivo experiments, mice were randomly divided into 4 groups: a control group, an EAT group, and two groups with LY294002 treatment (pTg plus 25 mg/kg or 50 mg/kg LY294002, respectively). The degrees of thyroiditis were evaluated, and the percentage of Th17 cells, expression of interleukin-17A (IL-17A), and the main components of the Notch-PI3K signaling pathway were detected in different groups. In vitro experiments, two different dosages of LY294002 (25 and 50 μM) were used to intervene splenic mononuclear cells (SMCs) from EAT mice to further evaluate the regulatory effect of Notch-PI3K pathway on Th17 cells.

Our data demonstrate that the infiltration of Th17 cells and the expressions of IL-17A, Notch, hairy and split 1 (Hes1), p‑AKT (Ser473), p‑AKT (Thr308), p‑mTOR (Ser2448), S6K1, and S6K2 increased remarkably in EAT mice. After PI3K pathway was blocked, the degrees of thyroiditis were significantly alleviated, and the proportion of Th17 cells, the expression of IL-17A, and the above Notch-PI3K pathway-related molecules decreased in a dose-dependent manner. Additionally, the proportion of Th17 cells was positively correlated with the concentration of serum thyroglobulin antibody (TgAb), IL-17A, and Notch-PI3K pathway-related molecules mRNA levels.

Notch signal promotes the secretion of IL-17A from Th17 cells by regulating the downstream PI3K/AKT/mTORC1 pathway through Hes-Phosphatase and tensin homolog (PTEN) and participates in thyroid autoimmune damage, and the PI3K pathway inhibitor may play important effects on AIT by affecting Th17 cells differentiation.

Interleukin-17 (IL-17)-producing helper T (TH17) cells are heterogenous and consist of nonpathogenic TH17 (npTH17) cells that contribute to tissue homeostasis and pathogenic TH17 (pTH17) cells that mediate tissue inflammation. Here, we characterize regulatory pathways underlying TH17 heterogeneity and discover substantial differences in the chromatin landscape of npTH17 and pTH17 cells both in vitro and in vivo. Compared to other CD4+ T cell subsets, npTH17 cells share accessible chromatin configurations with regulatory T cells, whereas pTH17 cells exhibit features of both npTH17 cells and type 1 helper T (TH1) cells. Integrating single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq), we infer self-reinforcing and mutually exclusive regulatory networks controlling different cell states and predicted transcription factors regulating TH17 cell pathogenicity. We validate that BACH2 promotes immunomodulatory npTH17 programs and restrains proinflammatory TH1-like programs in TH17 cells in vitro and in vivo. Furthermore, human genetics implicate BACH2 in multiple sclerosis. Overall, our work identifies regulators of TH17 heterogeneity as potential targets to mitigate autoimmunity.

Stem-like T cells are characterized by their ability to self-renew, survive long-term, and give rise to a heterogeneous pool of effector and memory T cells. Recent advances in single-cell RNA-sequencing (scRNA-seq) and lineage tracing technologies revealed an important role for stem-like T cells in both autoimmunity and cancer. In cancer, stem-like T cells constitute an important arm of the anti-tumor immune response by giving rise to effector T cells that mediate tumor control. In contrast, in autoimmunity stem-like T cells perform an unfavorable role by forming a reservoir of long-lived autoreactive cells that replenish the pathogenic, effector T-cell pool and thereby driving disease pathology. This review provides background on the discovery of stem-like T cells and their function in cancer and autoimmunity. Moreover, the influence of the microbiota and metabolism on the stem-like T-cell pool is summarized. Lastly, the implications of our knowledge about stem-like T cells for clinical treatment strategies for cancer and autoimmunity will be discussed.

Human immunodeficiency virus (HIV) infection remains an important global public health problem. About 40 million people are infected with HIV, and this infection caused about 630,000 deaths in 2022. The hallmark of HIV infection is the depletion of CD4+ T helper lymphocytes (Th cells). There are at least seven different Th subtypes, and not all are the main targets of HIV. Moreover, the effect of the virus in a specific subtype can be completely different from that of the others. Although the most compromised Th subtype in HIV infection is Th17, HIV can induce important dysregulations in other subtypes, such as follicular Th (Tfh) cells and regulatory Th cells (Treg cells or Tregs). Several studies have shown that HIV can induce an increase in the immunosuppressive activity of Tregs without causing a significant reduction in their numbers, at least in the early phase of infection. The increased activity of this Th subtype seems to play an important role in determining the immunodeficiency status of HIV-infected patients, and Tregs may represent a new target for innovative anti-HIV therapies, including the so-called "Kick and Kill" therapeutic method whose goal is the complete elimination of the virus and the healing of HIV infection. In this review, we report the most important findings on the effects of HIV on different CD4+ T cell subtypes, the molecular mechanisms by which the virus impairs the functions of these cells, and the implications for new anti-HIV therapeutic strategies.

Melioidosis caused by Burkholderia pseudomallei is an infectious disease with a high mortality rate. In acute melioidosis, sepsis is a major cause of death among patients. Once the bacterium enters the bloodstream, immune system dysregulation ensues, leading to cytokine storms. In contrast to B. pseudomallei, a closely related but non-virulent strain B. thailandensis has rarely been reported to cause cytokine storms or death in patients. However, the mechanisms in which the virulent B. pseudomallei causes sepsis are not fully elucidated. It is well-documented that monocytes play an essential role in cytokine production in the bloodstream. The present study, therefore, determined whether there is a difference in the innate immune response to B. pseudomallei and B. thailandensis during infection of primary human monocytes and THP-1 monocytic cells by investigating pyroptosis, an inflammatory death pathway known to play a pivotal role in sepsis. Our results showed that although both bacterial species exhibited a similar ability to invade human monocytes, only B. pseudomallei can significantly increase the release of cytosolic enzyme lactate dehydrogenase (LDH) as well as the increases in caspase-1 and gasdermin D activations in both cell types. The results were consistent with the significant increase in IL-1β and IL-18 production, key cytokines involved in pyroptosis. Interestingly, there was no significant difference in other cytokine secretion, such as IL-1RA, IL-10, IL-12p70, IL-15, IL-8, and IL-23 in cells infected by both bacterial species. Furthermore, we also demonstrated that ROS production played a crucial role in controlling pyroptosis activation during B. pseudomallei infection in primary human monocytes. These findings suggested that pyroptosis induced by B. pseudomallei in the human monocytes may contribute to the pathogenesis of sepsis in acute melioidosis patients.

Graves' disease is a prevalent thyroid disorder and is the primary cause of hyperthyroidism. Significant progress has been made in understanding the epidemiology, pathogenesis, diagnosis, treatment, and prognosis of this disease. However, bibliometric analyses on Graves' disease are lacking. We aimed to comprehensively summarize the research, progression, and focal points of Graves' disease through data mining and integrated analysis of the existing literature.

We retrieved relevant literature on Graves' disease from 2003 to 2023 from the Web of Science database. We performed bibliometric analysis using CiteSpace and the R package Bibliometrix.

We identified 10,901 publications from 132 countries, with a steady rise in the number of publications over the past 5 years. The US leads in publication volume, with the University of California System being the primary contributing institution. The journal Thyroid had the highest publication output, while the Journal of Clinical Endocrinology and Metabolism was the most frequently cited. These publications involved 2305 authors, with Antonelli Alessandro and Smith Terry being the most prolific. The most frequently cited articles were the "2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis" and the "Thyroid Association/European Group on Graves' orbitopathy guidelines for the management of Graves' orbitopathy." Analysis of the bursts of cited references, keywords, and their clustering revealed that research on Graves' disease predominantly centers on clinical management, thyroid-stimulating hormone receptors, thyroid hormones, autoimmunity and inflammation, Graves' ophthalmopathy, thyroid nodules, and thyroid cancer.

This is the first comprehensive bibliometric study to summarize progress and trends in Graves' disease research. These results highlight recent research hotspots and promising directions, thereby providing a valuable reference for other scholars.

Anthracene, a polycyclic aromatic hydrocarbon (PAH), is a widespread environmental pollutant that poses potential risks to human health. Exposure to anthracene can result in various adverse health effects, including skin-related disorders. Photo exposure sufficiently removes the anthracene from the environment but also generates more degradation products which can be more toxic. The goal of this study was to assess the change in anthracene dermotoxicity caused by photodegradation and understand the mechanism of this change. In the present study, over 99.99% of anthracene was degraded within 24 h of sunlight exposure, while producing many intermediate products including 9,10-anthraquinone and phthalic acid. The anthracene products with different durations of photo exposure were applied to 2D and 3D human keratinocyte cultures. Although the non-degraded anthracene significantly delayed the cell migration, the cell viability and differentiation decreased dramatically in the presence of the photodegraded anthracene. Anthracene photodegradation products also altered the expression patterns of a number of inflammation-related genes in comparison to the control cells. Among these genes, il1a, il1b, il8, cxcl2, s100a9, and mmp1 were upregulated whereas the tlr4 and mmp3 were downregulated by the photodegraded anthracene. Topical deliveries of the photodegraded and non-degraded anthracene to the dorsal skin of hairless mice showed more toxic effects by the photodegraded anthracene. The 4-hour photodegradation products of anthracene thickened the epidermal layer, increased the dermal cellularity, and induced the upregulation of inflammatory markers, il1a, il1b, s100a9, and mmp1. In addition, it also prevented the production of a gap junction protein, Connexin-43. All the evidence suggested that photodegradation enhanced the toxicities of anthracene to the skin. The 4-hour photodegradation products of anthracene led to clinical signs similar to acute inflammatory skin diseases, such as atopic and contact dermatitis, eczema, and psoriasis. Therefore, the potential risk of skin irritation by anthracene should be also considered when an individual is exposed to PAHs, especially in environments with strong sunlight.