Arsenic, a ubiquitous environmental toxicant, has been implicated in causing liver fibrosis through chronic exposure. Histone lactylation is involved in various inflammatory diseases, among which liver fibrosis is included, and is also closely related to the regulation of immune cells. This work focuses on the mechanisms of histone lactylation and Th17 cell differentiation in arsenite-induced liver fibrosis through animal and cellular experiments. Chronic arsenite exposure of mice led to liver fibrosis, elevated glycolysis in liver, and increased lactate levels in both serum and liver, which promoted Th17 cell differentiation of CD4+ T cells and increased IL-17A secretion. Treatment with oxamate, a lactate dehydrogenase inhibitor, suppressed Th17 cell differentiation and alleviated fibrosis in the liver. For HepG2 cells, arsenite exposure enhanced glycolysis and lactate levels, leading to increased global lactylation (Kla), H3K18la, interferon-regulatory factor 4 (IRF4), retinoic acid receptor-related orphan receptor gamma t (RORγt), and IL-17A expression and secretion in co-cultured Jurkat cells. Furthermore, in Jurkat cells, reducing lactate production and transport decreased these protein levels, suppressed Th17 cell differentiation, decreased IL-17A secretion, and ultimately inhibited the activation of hepatic stellate cells (HSCs). These results indicate that lactate derived from hepatocytes promotes Th17 cell differentiation by upregulating IRF4 through H3K18la, thereby enhancing IL-17A secretion and the activation of HSCs, contributing to arsenite-induced liver fibrosis. Our work reveals a new mechanism of histone lactylation in arsenite-induced liver fibrosis and offers a fresh perspective for the development of strategies for prevention and treatment of this condition.

Current subtyping methods of diffuse large B-cell lymphoma (DLBCL) could not satisfy the clinical demands for risk assessment and prognostic prediction. We aimed to investigate the prognostic effect of autophagy-related genes (ARGs) in DLBCL. Transcriptomic data of 1,409 DLBCL patients, 531 healthy controls (HCs), and single-cell sequencing data of 4 DLBCL were included. Validation involved spatial transcriptomics from 10 DLBCL patients and 110 DLBCL proteomic data from a local cohort. We identified 153 differentially expressed ARGs between DLBCL patients (n=48) and HCs (n=531), classifying 414 DLBCL patients into two subtypes based on autophagy heterogeneity. Subtype I, characterized by upregulated T regulatory (Treg) cells (P<0.0001) and T follicular helper (Tfh) cells (P=0.0012), showed a superior prognosis (P=0.035). Eight prognostic ARGs were selected to construct an autophagy-related model, dividing patients into low- and high-risk groups. Kaplan-Meier survival analysis revealed significantly better outcomes for the low-risk group in both the discovery (P<0.0001) and validation cohorts (P=0.0041). High-risk patients exhibited elevated IDO1 (P=0.042) and LAG3 (P<0.001) levels. Among the eight signature proteins, higher FAS was further verified to indicate a better prognosis in the local cohort (n=110) using antibody array (P=0.0083). FAS was primarily expressed in T cells such as Treg and Tfh cells and was elevated in non-progressive disease patients. FAS-positive T cells showed increased interferon-gamma (normalized enrichment score (NES)=2.196, FDR<0.0001) and alpha (NES=1.836, FDR<0.01) response activities. We constructed an autophagy-related model and identified FAS as a prognostic biomarker. FAS+ Treg and Tfh cell-enriched TME indicated a favorable prognosis.

Liver transplantation (LT) is a primary treatment option for patients with end-stage liver disease. However, post-transplantation immune regulation is critical to graft survival and long-term patient outcomes. Following liver transplantation, the recipient's immune system mounts a response against the graft, while the graft promotes anti-rejection immune reactions and the establishment of immune tolerance. In recent years, advances in the study of the immune microenvironment have provided new insights into post-transplantation immune regulation. Meanwhile, immunotherapy strategies have opened new possibilities for improving transplantation success rates and long-term survival. This review summarizes recent progress in understanding the immune microenvironment and immunotherapy following liver transplantation, focusing on key components of the transplant immune microenvironment, their regulatory networks and mechanisms, major immunosuppressive strategies, emerging immunotherapeutic approaches, and current challenges. The aim was to provide a theoretical foundation for optimizing clinical practice.

Defence from environmental threats is provided by physical barriers that confer mechanical protection and prevent the entry of microorganisms1. If microorganisms overcome those barriers, however, innate immune cells use toxic chemicals to kill the invading cells2,3. Here we examine immune diversity across tissues and identify a population of neutrophils in the skin that expresses a broad repertoire of proteins and enzymes needed to build the extracellular matrix. In the naive skin, these matrix-producing neutrophils contribute to the composition and structure of the extracellular matrix, reinforce its mechanical properties and promote barrier function. After injury, these neutrophils build 'rings' of matrix around wounds, which shield against foreign molecules and bacteria. This structural program relies on TGFβ signalling; disabling the TGFβ receptor in neutrophils impaired ring formation around wounds and facilitated bacterial invasion. We infer that the innate immune system has evolved diverse strategies for defence, including one that physically shields the host from the outside world.

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.

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.

Reproducing the pathophysiology of human multiple sclerosis (MS) in animal models is critical to identifying mechanisms triggering demyelination and to developing early intervention strategies. Here, we aimed to model overactivated Wnt (wingless-related integration site) signaling previously shown in postmortem brain tissues of patients with MS by inducing experimental autoimmune encephalomyelitis (EAE) in PdgfraCreER;Apcfl/fl and Olig2Cre;Apcfl/fl mice. These mice have overactivated Wnt signaling in oligodendrocyte precursor cells (OPCs) because of a conditional knockout of the pathway repressor adenomatous polyposis coli (APC). PdgfraCreER;Apcfl/fl EAE mice exhibited increased expression of markers for Wnt activation such as Axis inhibition protein 2 (AXIN2) and Wnt inhibitory factor 1 (WIF1) in OPCs and showed exacerbated EAE progression in both the spinal cord and the brain. Genetic or antibody-mediated ablation of CC-chemokine ligand 4 (CCL4) prevented infiltration of CD4+ T cells and arrested disease progression in these mice. A characterization of CNS (central nervous system) immune cell clusters identified an augmented subpopulation of NK1.1+CD11b+Gr-1+ cytotoxic macrophages in PdgfraCreER;Apcfl/fl EAE mice. Microinjection of this subpopulation of macrophages into the brains of wild-type C57/B6J mice was sufficient to induce demyelination. Ablation of CD4+ T cells prevented the effects of Wnt overactivation on demyelination and immune cell infiltration. Antagonizing chemokine receptor 5 (CCR5) using a European Medicines Agency-approved drug, maraviroc, reduced immune cell infiltration, alleviated demyelination, and attenuated EAE progression. We found an OPC-orchestrated immune cellular network that instigates early demyelination, provides insight into MS pathophysiology, and suggests avenues for early interventions.

The STAT3 is an important regulator in a wide range of different cell types. Human STAT3 variants are associated with several immune dysregulation diseases. The current study investigated the clinical, genetic, and immunobiological data obtained from a family with novel heterozygous STAT3 variants located at p.Y360C of the DNA binding domain. The clinical manifestations of these patients include autoimmunity, immunodeficiency, and postnatal growth defects. Broad STAT3 regulated cells including patient primary immune cells and HEK293 cells harboring the variant were assessed. Remarkably high levels of STAT3-regulated cytokines were detected in the sera of the patients. STAT3 nuclear binding and STAT3 activity were higher in STAT3-transduced HEK293 cells containing the p.Y360C variant when compared to HEK cells expressing wild type (WT) STAT3. Upon cytokine activation, STAT3 variants inhibited nuclear translocation of the WT STAT3 molecule. We also demonstrated that PBMCs from these patients exhibit significantly higher mitochondrial activity compared to that of healthy controls. The exploration of the effects of STAT3 Y360C variants described in our study provides novel insights into the molecular effects of the STAT3 variant and its role in the pathophysiology of STAT3 gain-of-function syndromes.

Transforming growth factor-β (TGF-β) plays a complex role in lung cancer pathophysiology, initially acting as a tumor suppressor by inhibiting early-stage tumor growth. However, its role evolves in the advanced stages of the disease, where it contributes to tumor progression not by directly promoting cell proliferation but by enhancing epithelial-mesenchymal transition (EMT) and creating a conducive tumor microenvironment. While EMT is typically associated with enhanced migratory and invasive capabilities rather than proliferation per se, TGF-β's influence on this process facilitates the complex dynamics of tumor metastasis. Additionally, TGF-β impacts the tumor microenvironment by interacting with immune cells, a process influenced by genetic and epigenetic changes within tumor cells. This interaction highlights its role in immune evasion and chemoresistance, further complicating lung cancer therapy. This review provides a critical overview of recent findings on TGF-β's involvement in lung cancer, its contribution to chemoresistance, and its modulation of the immune response. Despite the considerable challenges encountered in clinical trials and the development of new treatments targeting the TGF-β pathway, this review highlights the necessity for continued, in-depth investigation into the roles of TGF-β. A deeper comprehension of these roles may lead to novel, targeted therapies for lung cancer. Despite the intricate behavior of TGF-β signaling in tumors and previous challenges, further research could yield innovative treatment strategies.

Extracellular vesicles (EVs), including exosomes, mediate intercellular communication by transporting functional molecules between donor cells and recipient cells, thereby regulating biological processes, such as immune responses. miR-451a, an immune regulatory microRNA, is highly abundant in circulating EVs; however, its precise physiological significance remains to be fully elucidated. Here, we demonstrate that miR-451a deficiency exacerbates delayed-type hypersensitivity (DTH) in mice. Notably, miR-451a knockout resulted in a significant increase in the number of interleukin (IL)-17A-expressing T helper 17 and γδ T cells infiltrating DTH-induced ear lesions. miR-451a deficiency also increased the number of γδ T cells in the secondary lymphoid tissues. Comprehensive analyses revealed that miR-451 deficiency promoted the expression of Rorc and γδ T cell-related genes following sensitization with allergens. Moreover, intravenous administration of wild-type EVs to miR-451a knockout mice increased cellular miR-451a levels in tissues and significantly attenuated the severity of DTH. Furthermore, synthetic lipid nanoparticles encapsulating miR-451a effectively mitigated DTH. Our findings indicate the importance of circulating miR-451a in the proliferation of γδ T cells and highlight the therapeutic potential of lipid nanoparticle-based microRNA delivery platforms for interventions in immune-related diseases.

Microbial, especially fungal, sensitization has been associated with the development and exacerbation of treatment-refractory neutrophilic asthma. Among the airway-inhabiting fungi, Aspergillus fumigatus and Candida albicans are the dominant species that elicit protective T helper (Th) 17 and other T cell responses, contributing to airway neutrophilia and steroid resistance. However, it is not fully understood how fungal airway colonization impacts the immunopathogenesis of asthma. Here, we used a neutrophilic asthma model induced by C. albicans to study the immune regulation of this disease. We found that intranasal administration of C. albicans induced platelet infiltration into the lung. Platelet-expressed latent TGF-β could be activated specifically by Th17 cells and drive the commitment, maintenance, and expansion of Th17 cells. In Candida-induced asthma, an adoptive transfer of platelets enhanced Th17 responses, increasing airway neutrophil influx. Thus, managing airway mycobiota and reducing platelet intrapulmonary infiltration may serve as a promising interventional approach.

IL-17A has been implicated as a critical pro-inflammatory cytokine in the pathogenesis of autoimmune and neurodegenerative disorders. Emerging evidence indicates its capacity to activate microglial cells and astrocytes, subsequently inducing the production of inflammatory mediators that exacerbate neuronal injury and functional impairment. Clinical observations have revealed a demonstrated association between IL-17A concentrations and blood-brain barrier (BBB) dysfunction, creating a pathological feedback loop that amplifies neuro-inflammatory responses. Recent advances highlight the cytokine's critical involvement in neurodegenerative disorders through multiple molecular pathways. Therapeutic interventions utilizing monoclonal antibodies (mAbs) against IL-17A or its cognate receptor (IL-17R) have shown promising clinical potential. This review systematically examines the IL-17A-mediated neuro-inflammatory cascades; the mechanistic contributions to neurodegenerative pathology in the established disease models including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis; and current therapeutic strategies targeting the IL-17A signaling pathways. The analysis provides novel perspectives on optimizing cytokine-directed therapies while identifying the key challenges and research priorities for translational applications in neurodegeneration.

Primary sclerosing cholangitis (PSC) is a rare immune-mediated hepatobiliary disease, characterised by progressive biliary fibrosis, cirrhosis, and end-stage liver disease. As yet, no licensed pharmacological therapy exists. While significant advancements have been made in our understanding of the pathophysiology, the exact aetiology remains poorly defined. Compelling evidence from basic science and translational studies implicates the role of T helper 17 cells (Th17) and the interleukin 17 (IL-17) pro-inflammatory signalling pathway in the pathogenesis of PSC. However, exploration of the safety and efficacy of inhibiting the IL-17 pathway in PSC is lacking.

This is a phase 2a, open-label, multicentre pilot study, testing the safety of brodalumab, a recombinant human monoclonal antibody that binds with high affinity to interleukin-17RA, in adults with PSC. This study will enrol 20 PSC patients across five large National Health Service tertiary centres in the UK. The primary outcome of the study relates to determining the safety and feasibility of administering brodalumab in early, non-cirrhotic PSC patients. Secondary efficacy outcomes include non-invasive assessment of liver fibrosis, changes in alkaline phosphatase values and other liver biochemical readouts, assessment of biliary metrics through quantitative MR cholangiography+, and quality of life evaluation on completion of follow-up (using the 5D-itch tool, the PSC-patient-reported outcome and PSC-specific Chronic Liver Disease Questionnaire).

Ethical approval for this study has been obtained from the London Bridge Research Ethics Committee (REC23/LO/0718). Written informed consent will be obtained from all trial participants prior to undertaking any trial-specific examinations or investigations. On completion of the study, results will be submitted for publication in peer-reviewed journals and presented at national and international hepatology meetings. A summary of the findings will also be shared with participants and PSC communities.

ISRCTN15271834.

The Transforming Growth Factor-beta (TGF-β) signaling pathway, with SMAD4 as its central mediator, plays a pivotal role in regulating cellular functions, including growth, differentiation, apoptosis, and immune responses. While extensive research has elucidated SMAD4's role in tumorigenesis, its functions within immune cells remain underexplored. This review synthesizes current knowledge on SMAD4's diverse roles in various immune cells such as T cells, B cells, dendritic cells, and macrophages, highlighting its impact on immune homeostasis and pathogen response. Understanding SMAD4's role in immune cells is crucial, as its dysregulation can lead to autoimmune disorders, chronic inflammation, and immune deficiencies. The review emphasizes the significance of SMAD4 in immune regulation, proposing that deeper investigation could reveal novel therapeutic targets for immune-mediated conditions. Insights into SMAD4's involvement in processes like T cell differentiation, B cell class switch recombination, and macrophage polarization underscore its potential as a therapeutic target for a range of diseases, including autoimmune disorders and cancer.

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.

Atopic dermatitis (AD) is a common inflammatory dermatitis of the skin and poses therapeutic challenges due to the adverse reactions and high costs associated with available treatments. In Eastern Asian countries, a plethora of herbal remedies is extensively employed for the alleviation of AD. Many of these botanicals are renowned for their formidable anti-inflammatory properties, contributing to AD management. Chinese herbal medicine (CHM) and its active ingredients exhibit both prophylactic and therapeutic promise against AD by modulating inflammatory response, orchestrating immune system functions, and enhancing antioxidant activities. A comprehensive exploration of the underlying mechanisms involved in CHM treatment can enhance the comprehension of AD pathogenesis and facilitate the development of innovative drugs for AD. This study aims to elucidate the signaling pathways and potential targets implicated in CHM-based treatment of AD, providing a systematic theoretical framework for its application in therapy while serving as a valuable reference for developing more effective and safer AD therapeutic agents.

Plastic materials are ubiquitous, leading to constant human exposure to plastic additives such as plasticizers. There is growing evidence that plasticizers may contribute to obesity due to their disruptive effects on metabolism. Alternatives like diisononylcyclohexane-1,2-dicarboxylate (DINCH) are replacing traditional phthalates such as di-(2-ethylhexyl) phthalate (DEHP), which are now banned due to their proven harmful health effects. While DINCH is considered a safer alternative to DEHP and no adipogenic effects have been demonstrated in in vivo studies, recent research suggests that the primary metabolite, monoisononylcyclohexane-1,2-dicarboxylic acid ester (MINCH), promotes adipocyte differentiation and dysfunction in vitro. However, metabolic and molecular effects are not fully understood in vivo. Here, we performed a comprehensive in vivo analysis using C57BL/6N mice to investigate the effects of DINCH on adipose tissue physiology and function. Mice were exposed to two doses of DINCH for 16 weeks, followed by a 10-week recovery period. Tissue analysis confirmed the presence of DINCH and MINCH in liver and adipose tissue after treatment and recovery. After the recovery period, elevated DINCH concentrations in adipose tissue depots indicated possible bioaccumulation. Although no changes were observed in body composition and energy expenditure, sex-specific metabolic effects were identified. Female mice exhibited impaired whole-body insulin sensitivity and higher triglyceride levels, while male mice showed an altered insulin/C-peptide ratio and elevated cholesterol, HDL, and LDL levels. Proteomic profiling of serum, adipose and liver tissues revealed changes in pathways related to central energy metabolism and immune response, highlighting the systemic impact of DINCH, potentially on inflammatory processes. Most effects of DINCH, such as changes in insulin response and serum lipid levels, were diminished after the recovery period. Despite many findings consistent with the existing literature suggesting DINCH as a safer DEHP substitute, the observed sex-specific effects on insulin sensitivity, lipid metabolism and inflammatory processes, as well as potential bioaccumulation and long-term metabolic effects of DINCH exposure warrant careful consideration in further risk assessment.

Transforming growth factor beta (TGF-β) is a pluripotent cytokine expressed by all cells of the human body which plays important roles in maintaining homeostasis and allowing for proper individual development. Disturbances in TGF-β signaling contribute to the development of many diseases and disorders, including cancer and organ fibrosis. One of the diseases with the best-characterized correlation between TGF-β action and etiopathogenesis is asthma. Asthma is the most common chronic inflammatory disease of the lower and upper respiratory tract, characterized by bronchial hyperresponsiveness to a number of environmental factors, leading to bronchospasm and reversible limitation of expiratory flow. TGF-β, in particular TGF-β1, is a key factor in the etiopathogenesis of asthma. TGF-β1 concentration in bronchoalveolar lavage fluid samples is elevated in atopic asthma, and TGF-β expression is increased in asthmatic bronchial samples. The expression of all TGF-β isoforms is affected by a number of single nucleotide polymorphisms found in the genes encoding these cytokines. Some of the SNPs that alter the level of TGF-β expression may be associated with the occurrence and severity of symptoms of asthma and other diseases. The TGF-β gene polymorphisms, which are the subject of this paper, are potential diagnostic factors. If properly used, these polymorphisms can facilitate the early and precise diagnosis of asthma, allowing for the introduction of appropriate therapy and reduction of asthma exacerbation frequency.

Ankylosing spondylitis (AS) is an autoimmune rheumatic disease that primarily affects the axial joints, with its etiology complex and still not fully understood. The unknown pathogenesis of AS limits the development of treatment strategies, so keeping up-to-date with the current research on AS can help in searching for potential therapeutic targets. In addition to the classic HLA-B27 genetic susceptibility and Th17-related inflammatory signals, increasing research is focusing on the influence of autoantigen-centered autoimmune responses and bone stromal cells on the onset of AS. Autoantigens derived from gut microbiota and preferential TCR both exacerbate the autoimmune response in patients with AS. Furthermore, dysregulated bone metabolism also promotes pathological new bone formation in AS. Current treatments approved for AS almost focus on the management of inflammation with inconsistent treatment results due to the heterogeneity of patients. In this review, we systematically summarized various pathogenesis and management of AS, meanwhile discussed the underlying risk factors and potential therapeutic targets.

Dysregulation of Th17 and Treg cells contributes to the pathophysiology of cerebral ischemia. Metabolic changes of peripheral CD4+ T cells lead to the imbalance of Treg/Th17 polarization, which represents a promising strategy for post-stroke therapy. Polyphyllin VII (PVII), a steroidal saponin extracted from traditional Chinese herb Rhizoma Paridis, has multiple bioactivities, but the potential function of PVII in cerebral ischemia-reperfusion injury is not elucidated yet. In our study, a mouse transient middle cerebral artery occlusion (MCAO) model was constructed. TTC staining, H&E staining, TUNEL staining, ELISA assay, flow cytometry, western blot, RT-qPCR, Open-field test, Morris water maze test, hanging wire test, rotarod test and foot-fault test were performed to evaluate the potential function of PVII in MCAO mice. We found that PVII showed protective effects on cerebral ischemia-reperfusion injury by reducing infarct volume, ameliorating brain injury and neuroinflammation, and improving long-term functional recovery of MCAO mice. PVII promoted Treg infiltration and suppressed infiltration of Th1/Th17 cells in ischemic brain in vivo. Moreover, PVII impaired peripheral CD4+ T cell activation and modulated Treg/Th17 differentiation in vitro. Mechanistically, PVII suppressed mTORC1 activation to influence glycolytic metabolism and ROS generation of T cells, thus leads to the imbalance of Treg/Th17 polarization towards Treg skewed. Furthermore, reactivation of mTORC1 by MHY1485 abolished the influence of PVII on brain injury and neuroinflammation in MCAO mice. Our data provided a novel role of PVII in cerebral ischemia-reperfusion injury via manipulating Treg/Th17 imbalance.

The CD4+ T-cell population plays a vital role in the adaptive immune system by coordinating the immune response against different pathogens. A significant transformation occurs in CD4+ cells during an immune response, as they shift from a dormant state to an active state. This transformation leads to extensive proliferation, differentiation, and cytokine production, which contribute to regulating and coordinating the immune response. Th17 and Treg cells are among the most intriguing CD4+ T-cell subpopulations in terms of genetics and metabolism. Gene expression modulation processes rely on and are linked to metabolic changes in cells. Lactylation is a new model that combines metabolism and gene modulation to drive Th17/Treg differentiation and functional processes. The focus of this review is on the metabolic pathways that impact lymphocyte gene modulation in a functionally relevant manner.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by an isolated thrombocytopenia and variable phenotype as some patients suffer no bleeding whilst others have bleeding from mild to severe, which may be fatal. This variability probably reflects the disease's complex pathophysiology; a dysregulated hyperreactive immune effector cell response involving the entire adaptive immune system (e.g. B and T cell subsets) that leads to platelet and megakaryocyte (MK) destruction. It appears that these effector responses are due to a breakdown in immune tolerance, and this is characterized by defects in several immunosuppressive cell types. These include defective T regulatory cells (Tregs), B regulatory cells (Bregs) and Myeloid-derived suppressor cells (MDSC), all of which are all intimately associated with antigen presenting cells (APC) such as dendritic cells (DC). The loss of this immunosuppressive axis allows for the activation of unchecked autoreactive T cells and B cells, leading to the development of autoantibodies and cytotoxic T cells (CTL), which can directly destroy platelets in the periphery and inhibit MK platelet production in the bone marrow (BM). This review will focus on the effector cell mechanisms in ITP and highlight the defective immunosuppressive axis that appears responsible for this platelet-specific immune hyperreactivity.

Inappropriate CD4+ T helper (TH) cell differentiation leads to progression of inflammatory and autoimmune diseases, yet the regulatory mechanisms governing stability and activity of transcription factors controlling TH cell differentiation remain elusive. Here, we describe how pseudokinase serine threonine kinase 40 (STK40) facilitates TH1/TH17 differentiation under pathological conditions. STK40 in T cells is dispensable for immune homeostasis in resting mice. However, mice with T cell-specific deletion of STK40 exhibit attenuated symptoms of experimental autoimmune encephalomyelitis and colitis, accompanied by diminished TH1 and TH17 cell differentiation. Mechanistically, STK40 facilitates K48-linked polyubiquitination and proteasomal degradation of FOXO1/4 through promoting their interaction with E3 ligase COP1. Inhibition of FOXO4 or FOXO1, respectively, restores differentiation potential of STK40-deficient TH1/TH17 cells. Together, our data suggest a crucial role of STK40 in TH1 and TH17 cell differentiation, thereby enabling better understanding of the molecular regulatory network of CD4+ T cell differentiation and providing effective targets for the treatment of autoimmune diseases.

The IL-23 signaling pathway in both innate and adaptive immune cells is vital for orchestrating type 17 immunity, which is marked by the secretion of signature cytokines such as IL-17, IL-22, and GM-CSF. These proinflammatory mediators play indispensable roles in maintaining intestinal immune equilibrium and mucosal host defense; however, their involvement has also been implicated in the pathogenesis of chronic inflammatory disorders, such as inflammatory bowel diseases and autoimmunity. However, the implications of type 17 immunity across diverse inflammation models are complex. This review provides a comprehensive overview of the multifaceted roles of these cytokines in maintaining gut homeostasis and in perturbing gut barrier integrity, leading to acute and chronic inflammation in various models of gut infection and colitis. Additionally, this review focuses on type 17 immunity interconnecting multiple organs in autoimmune conditions, with a particular emphasis on the pathogenesis of autoimmune arthritis and neuroinflammation driven by T cells primed within the gut microenvironment.

This Pillars of Immunology article is a commentary on "Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis," a pivotal article written by H. R. Conti, F. Shen, N. Nayyar, E. Stocum, J. N. Sun, M. J. Lindemann, A. W. Ho, J. H. Hai, J. J . Yu, J. W. Jung, S. G. Filler, P. Masso-Welch, M. Edgerton, and S. L. Gaffen, and published in The Journal of Experimental Medicine in 2009. https://doi.org/10.1084/jem.20081463.

Cow's milk allergy is one of the most common food allergies in children, and its pathomechanism is still under investigation. Recently, an increasing number of studies have linked food allergy to intestinal barrier dysfunction. The present study aimed to investigate changes in the intestinal microenvironment during the development of β-lactoglobulin (β-lg) allergy under conditions of early intestinal dysfunction.

BALB/c mice received intraperitoneal β-lg with Freund's adjuvant, followed by oral β-lg while receiving dextran sulphate sodium salt (DSS) in their drinking water (0.2% w/v). The immunized group without DSS and the groups receiving saline, oral β-lg, or DSS served as controls.

The study showed that the immunization effect was greater in mice with mild intestinal barrier dysfunction. Although DSS did not affect the mice's humoral response to β-lg, in combination with β-lg, it significantly altered their cellular response, affecting the induction and distribution of T cells in the inductive and peripheral tissues and the activation of immune mediators. Administration of β-lg to sensitized mice receiving DSS increased disease activity index (DAI) scores and pro-inflammatory cytokine activity, altered the distribution of claudins and zonulin 1 (ZO-1) in the colonic tissue, and negatively affected the balance and activity of the gut microbiota.

The research model used appears attractive for studying food allergen sensitization, particularly in relation to the initial events leading to mucosal inflammation and the development of food hypersensitivity.

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.

STAT3 gain-of-function (GOF) variants results in a heterogeneous clinical syndrome characterized by early onset immunodeficiency, multi-organ autoimmunity, and lymphoproliferation. While 191 documented cases with STAT3 GOF variants have been reported, the impact of individual variants on immune regulation and the broad clinical spectrum remains unclear. We developed a Stat3p.L387R mouse model, mirroring a variant identified in a family exhibiting common STAT3 GOF symptoms, and rare phenotypes including pulmonary hypertension and retinal vasculitis. In vitro experiments revealed increased STAT3 phosphorylation, nuclear migration, and DNA binding of the variant. Our Stat3p.L387R model displayed similar traits from previous Stat3GOF strains, such as splenomegaly and lymphadenopathy. Notably, Stat3p.L387R/+ mice exhibited heightened embryonic lethality compared to prior Stat3GOF/+ models and ocular abnormalities were observed. This research underscores the variant-specific pathology in Stat3p.L387R/+ mice, highlighting the ability to recapitulate human STAT3 GOF syndrome in patient-specific transgenic murine models. Additionally, such models could facilitate tailored treatment development.

Approximately 25% of cancers are preceded by chronic inflammation that occurs at the site of tumor development. However, whether this multifactorial oncogenic process, which commonly occurs in the intestines, can be initiated by a specific immune cell population is unclear. Here, we show that an intestinal T cell subset, derived from interleukin-17 (IL-17)-producing helper T (TH17) cells, induces the spontaneous transformation of the intestinal epithelium. This subset produces inflammatory cytokines, and its tumorigenic potential is not dependent on IL-17 production but on the transcription factors KLF6 and T-BET and interferon-γ. The development of this cell type is inhibited by transforming growth factor-β1 (TGFβ1) produced by intestinal epithelial cells. TGFβ signaling acts on the pretumorigenic TH17 cell subset, preventing its progression to the tumorigenic stage by inhibiting KLF6-dependent T-BET expression. This study therefore identifies an intestinal T cell subset initiating cancer.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gastrointestinal tract. The introduction of biologics, particularly anti-interleukin (IL) agents, has revolutionized IBD treatment. This review summarizes the role of ILs in IBD pathophysiology and describes the efficacy and positioning of anti-IL therapies. We discuss the functions of key ILs in IBD and their potential as therapeutic targets. The review then discusses anti-IL therapies, focusing primarily on ustekinumab (anti-IL-12/23), risankizumab (anti-IL-23), and mirikizumab (anti-IL-23). Clinical trial data demonstrate their efficacy in inducing and maintaining remission in Crohn's disease and ulcerative colitis. The safety profiles of these agents are generally favorable. However, long-term safety data for newer agents are still limited. The review also briefly discusses emerging therapies such as guselkumab and brazikumab. Network meta-analyses suggest that anti-IL therapies perform well compared to other biological agents. These agents may be considered first- or second-line therapies for many patients, especially those with comorbidities or safety concerns. Anti-IL therapies represent a significant advancement in IBD treatment, offering effective and relatively safe options for patients with moderate to severe disease.

Parkinson's disease (PD) is the second leading neurodegenerative disease after Alzheimer's disease. Mucuna pruriens (L.) DC. (MP) is a plant that contains Levodopa (L-DOPA) and has been known to improve the symptoms of PD. In this preliminary study, we investigated the anti-parkinsonian potential of MP to compare the effects of L-DOPA. We first developed an in vivo model of the PD in C57BL/6 male mice using rotenone. A total of twelve mice were used for this experiment. Nine mice were injected with rotenone (28 mg/kg) daily for 28 days. The mice experiments were performed to validate the effectiveness of MP to treat PD. Synthetic L-DOPA in a ratio of 1:20 with MP was used as MP contains 5% L-DOPA by weight in it. MP and L-DOPA were injected for 19 days on a daily basis. Cognitive function was evaluated using beam balance and olfactory tests. Serum analysis was performed using serum enzyme-linked immunosorbent assay (ELISA) analysis test. IL-12, IL-6, and TGF-β 1 were evaluated to validate the PD inducement and treatment. The levels of IL-12, IL-6, and TGF-β1 (p < 0.0001) in the PD mice group were significantly higher than those in the control group. The PD mice also showed higher latencies in beam balance and olfactory tests (p < 0.0001) compared to the control group. Both MP and L-DOPA-treated groups showed alleviation in latencies in beam balance and olfactory tests and decreased neuroinflammation in ELISA analysis (p < 0.001). The results treated by MP and L-DOPA showed insignificant differences in their values (p > 0.05). This proved that the MP and L-DOPA had similar effects in improving the symptoms of PD when used in the ratio of 1:20. Furthermore, both MP and L-DOPA reduced the level of IL-6 and TGF-β1 in this study. It may be inferred that a reduction in the level of IL-6 and TGF-β1 eventually leads to a reduction in the Th17 cells. The pathogenic Th17 is thought to be present in virtually all chronic inflammatory disorders. This can be an interesting area of research in further understanding the immunological effect of MP in ameliorating PD symptoms.

The high-affinity IgE receptor, FcεRI, is typically associated with type 2 effectors such as mast cells (MC). The relatively unique expression profile of FcεRI and accumulating evidence from pre-clinical and clinical settings, such as MC interactions with tumors, have led us to study MCs as a potential therapeutic target in breast cancer. Our work identified MCs interacting with tumor cells at primary sites using the 4T1 (BALB/c) adenocarcinoma model in vivo. However, this analysis was complicated by a surprising finding that the tumor cells intrinsically and strongly expressed FcεRI. We further studied the expression and function of FcεRI in breast cancer cells in vitro. The 4T1 cells expressed FcεRI to a level similar to mouse bone marrow-derived MC (BMMC). Additionally, two established breast cancer cultures derived from human T-47D cells, one estrogen-dependent (E3) and the other estrogen-withdrawn (EWD8), also expressed FcεRI with EWD8 cells showing the greatest abundance. Functional analyses indicated that IgE-mediated antigen stimulation did not elicit classic Ca2+ flux in breast cancer cells as seen in the respective species' MCs; however, FcεRI crosslinking could stimulate IL-6 production from the T-47D derivatives. Preliminary analysis of primary breast cancer biopsy datasets using R2: Genomics Analysis and Visualization Platform was discordant with our in vivo model and in vitro observations. Indeed, FcεRI mRNA abundance declined in metastatic breast cancers compared to non-cancerous breast tissue. Altogether, we report a previously unidentified and immunologically substantive difference between breast cancer models and human primary tumors. Investigators pursuing FcεRI-relevant therapeutics in this context should be aware of this translational barrier.

Parkinson's disease (PD) is the second most common neurodegenerative disease, and its hallmark pathological features are the loss of dopaminergic (DA) neurons in the midbrain substantia nigra pars compacta (SNpc) and the accumulation of alpha-synuclein (α-syn). It has been shown that the integrity of the blood-brain barrier (BBB) is damaged in PD patients, and a large number of infiltrating T cells and inflammatory cytokines have been detected in the cerebrospinal fluid (CSF) and brain parenchyma of PD patients and PD animal models, including significant change in the number and proportion of different CD4+ T cell subsets. This suggests that the neuroinflammatory response caused by CD4+ T cells is an important risk factor for the development of PD. Here, we systematically review the differentiation of CD4+ T cell subsets, and focus on describing the functions and mechanisms of different CD4+ T cell subsets and their secreted cytokines in PD. We also summarize the current immunotherapy targeting CD4+ T cells with a view to providing assistance in the diagnosis and treatment of PD.

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.