Triple-negative breast cancer (TNBC) possesses high malignant and metastatic rates among all subtypes. Chemotherapy is a standard of care for TNBC but only a small moiety of patients achieved complete relief (CR) after chemotherapy. The recent concept of tumor ecosystem has provided new insights into solutions from an approach of enhancing anti-tumoral immunity of macrophages. We hereby observed a positive correlation of YTHDC2 abundance with anti-tumoral gene markers of macrophages. YTHDC2-high macrophages also exerted interactions with other immune cells such as T helper cells, cytotoxic T cells, and NK cells. Further investigation on the transcriptional regulatory network identified six transcriptional factors upregulated by YTHDC2, and they together influenced the expressions of TWISTNB and the oncogene MYC. Additionally, our survival analysis prompted that YTHDC2 is prognostic of higher chemo-therapeutic efficacy and better survival outcomes. We demonstrated that ample macrophage YTHDC2 indicates anti-tumoral phenotype polarization and propitious survival outcome in post-treatment TNBC patients (Clinical trial registry name: Chinese Clinical Trial Registry, Registration No.: ChiCTR2400084513, Registration Date: 2024-05-20).

The development of antigen-specific immunotherapy for autoimmune diseases constitutes an important unmet clinical need. Here we present an innovative inverse vaccine platform leveraging epigenetic reprogramming to induce durable antigen-specific immune tolerance. This inverse vaccine (mDCNVreg) is constructed using artificial cell membrane nanovesicles derived from IFN-γ-primed regulatory dendritic cells subjected to epigenetic modulation. The engineered mDCNVreg features upregulated MHC-II expression enabling targeted antigen presentation, suppressed costimulatory molecules expression, and an enhanced coinhibitory molecules display. Through coordinated mechanisms involving enhanced lymphoid trafficking and phenotype stabilization, this platform significantly enhances antigen delivery to secondary lymphoid organs while maintaining tolerogenic potency. Crucially, mDCNVreg directly induces CD4+ T cell clonal anergy through epitope-specific interactions, establishing long-lasting immune tolerance. This work demonstrates a promising epigenetic engineering approach for reverse vaccine design in personalized autoimmune disease therapy.

The systemic immune-inflammation index (SII) is a newly identified marker of inflammation., and the relationship between chronic bronchitis (CB) and inflammation is closely associated. However, the influence of SII on CB remains unclear at present.This cross-sectional study was conducted using data from individuals with complete SII and CB records from the 2001-2018 National Health and Nutrition Examination Survey (NHANES). Binary weighted logistic regression was employed to investigate the relationship between SII and CB risk. Additionally, restricted cubic spline regression models and segmented regression models were used to examine nonlinear relationships and threshold effects. Receiver operating characteristic (ROC) curves were adopted to evaluate the predictive value of SII for CB. Stratified analysis was adopted to assess the association between SII and CB in different populations. After adjusting for all covariables, there was a significant positive relevance observed between log-transformed SII (log (SII)) with CB (OR = 1.52, 95% CI: 1.27-1.82, P < 0.001). A nonlinear dose-response relationship with the threshold of 8.14 was observed between log (SII) and CB risk. When log (SII) exceeded 8.14, each unit increase in log (SII) was associated with a 1.31-fold increase in the risk of CB (OR = 1.31, 95% CI: 1.22-1.40, P < 0.001). Furthermore, ROC curves revealed strong predictive capability of SII for CB (AUC = 0.729). Elevated SII levels are associated with an increased prevalence of CB. Furthermore, a non-linear association exists between SII and the increased risk of CB.

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy, and the current treatment strategies have poor efficacy. Pyroptosis, a type of immunogenic cell death, significantly enhances antitumor immunity by triggering the release of numerous intracellular components. Here, we prepared a covalent-organic framework (COF) loaded with doxorubicin (DOX) and coated it with hyaluronic acid (HA) as a therapeutic delivery system (HA@DOX-COF) for the treatment of TNBC. Mechanistically, upon cellular uptake, HA@DOX-COF activated pyroptosis through the caspase-3/GSDME pathway. Moreover, HA@DOX-COF induced a pyroptosis-induced antitumor immune response and further augmented the efficacy of immune checkpoint blockade (ICB). Our results demonstrated that the combination of HA@DOX-COF and an anti-PD-1 antibody markedly inhibited tumor progression in a TNBC murine model. Overall, our work offers a potential approach for pyroptosis-induced immunotherapy for TNBC, which may increase the efficacy of ICB-based immunotherapy.

This study aimed to investigate the inhibitory effect of estradiol (E2) on acute cellular rejection following murine cervical heart transplantation and the role of G protein-coupled estrogen receptor 1 (GPER1).

A murine cervical heart transplantation model was established and categorized into four groups: syngeneic group (C57BL/6 to C57BL/6), allogenic control group (BALB/c to C57BL/6), E2 group (BALB/c to C57BL/6), and E2 + G15 group (G15: one of GPER1 blocker) (BALB/c to C57BL/6). Survival time, pathological rejection grade, intimal hyperplasia area of coronary artery in donor heart, mRNA expression levels of TGF-β, IL-10, and Foxp3 in spleen, and protein expression levels of CD4 and CD25 in spleen membrane proteins, were compared among these groups.

The syngeneic group showed 100% survival, while survival in the allogenic control group was significantly reduced. E2 treatment prolonged survival compared to the allogenic control group, but survival decreased with the addition of E2 + G15. Rejection was reduced in the E2 group compared to the allogenic control group, whereas the E2 + G15 group exhibited increased rejection compared to the E2 group. Intimal hyperplasia was absent in the syngeneic group, significant in the allogenic control group, reduced in the E2 group compared to the allogenic control group, but greater in the E2 + G15 group compared to the E2 group. The expression of IL-10, Foxp3, and TGF-β in the allogenic control group was higher than in the syngeneic group. In the E2 group, IL-10, Foxp3, and CD25 were higher than in the allogenic control group, while TGF-β and CD4 expression were lower. The E2 + G15 group had lower IL-10, Foxp3, and CD25 expression but higher TGF-β expression than the E2 group.

Severe acute cellular rejection was observed following murine cervical heart transplantation. E2 suppresses acute rejection by enhancing Treg cell expression, mediated by GPER1.

Microsatellites are essential genomic components increasingly linked to transcriptional regulation. FoxP3, a transcription factor critical for regulatory T cell (Treg) development, recognizes TTTG repeat microsatellites by forming multimers along DNA. However, FoxP3 also binds a broader range of TnG repeats (n = 2-5), often at the edges of accessible chromatin regions. This raises questions about how FoxP3 adapts to sequence variability and the potential role of nucleosomes. Using cryoelectron microscopy and single-molecule analyses, we show that murine FoxP3 assembles into various distinct supramolecular structures, depending on DNA sequence. This structural plasticity enables FoxP3 to bridge 2-4 DNA duplexes, forming ultrastable structures that coordinate multiple genomic loci. Nucleosomes further facilitate FoxP3 assembly by inducing local DNA bending, creating a nucleus that recruits distal DNA elements through multiway bridging. Our findings thus reveal FoxP3's unusual ability to shapeshift to accommodate evolutionarily dynamic microsatellites and its potential to reinforce chromatin boundaries and three-dimensional genomic architecture.

Intestinal fibrosis is a serious complication of Crohn's disease (CD), often resulting from chronic inflammation. However, the precise mechanisms through which inflammation induces intestinal fibrosis remain inadequately elucidated.

A comprehensive single-cell atlas of full-thickness CD, provided by Dr. Florian Rieder, was subjected to reanalysis. Our study used a DSS-induced chronic colitis model in both wild-type (WT) and Areg-/- mice. Additionally, a CD45RBhi CD4+ T cell adoptive transfer model involving WT and Areg-/- Treg cells (Tregs) was used. The expressions of AREG in CD with or without intestinal fibrosis, Tregs and human intestinal myofibroblasts (MFs) were determined. The effect of AREG on proliferation/migration/activation in human intestinal MFs was determined.

Several types of cells were differentially expressed between stricture and non-stricture CD. Among T cells, Tregs accounted for a larger proportion and were significantly increased in stenotic tissues of stricture CD. Although DSS-induced colitis was more severe in Areg-/- mice, which developed less severe intestinal fibrosis compared with WT mice. The transfer of Areg-/- Tregs resulted in less severe fibrosis in Rag-/- mice than WT Tregs. Moreover, TGF-β stimulated AREG expression in Tregs and human intestinal MFs via activation of Smad3.

These findings demonstrated that AREG derived from Tregs and human intestinal MFs, induced by TGF-β, amplifies intestinal fibrotic reactions in experimental colitis as well as in human CD patients. Thus, the TGF-β-Smad3-AREG pathway could be a potential therapeutic target for treating fibrosis in CD.

Graft-versus-Host Disease (GvHD) is the main cause of morbidity and mortality of allogeneic hematopoietic cell transplantation (allo-HCT). Conventional immunosuppressive pharmacotherapy remains the backbone of GvHD prevention and treatment with suboptimal outcomes especially for patients with refractory disease. Adoptive immunotherapy with regulatory T-cells (Treg) stands as an alternative approach that aims to restore immune tolerance and circumvent prolonged immunosuppression albeit preserving the beneficial Graft-versus-Leukaemia (GvL) effect. In this review, we summarise recent knowledge on Treg biology, clinical applications of various Tregs subtypes in the setting of GvHD and future endeavours of the field.

Unexplained recurrent spontaneous abortion (URSA) involves multifactorial etiologies, with regulatory T cells (Tregs) playing a pivotal role in maintaining immune tolerance during pregnancy. Baicalein, a flavonoid from Scutellaria baicalensis, exhibits anti-inflammatory and immunomodulatory properties. This study evaluates baicalein's therapeutic potential in mitigating URSA via the TLR4/NF-κB signaling pathway.

A URSA mouse model was used, and baicalein was administered intraperitoneally. Pregnancy outcomes, abortion rates, and placental morphology were assessed on gestational day 14 (G14). Treg cells were quantified via flow cytometry, and gene/protein expression levels were analyzed by immunohistochemistry, Western blotting, and real-time PCR. In vitro experiments on ihESCs further investigated the role of the TLR4/NF-κB pathway.

Baicalein reduced abortion rates from 33.3 % in URSA mice to 21.6 % (low dose) and 14.8 % (high dose), improved embryonic development by altering placental structure and decidual morphology, and reduced inflammation at the maternal-fetal interface. It expanded Treg cells and enhanced the expression of IGFBP-1 and PRL, markers of endometrial decidualization, and decreased TLR4, p-P65, and P65 expression. In vitro, baicalein's effects were abrogated by TLR4 inhibition, confirming pathway specificity.

Baicalein improved pregnancy outcomes by enhancing Treg function and promoting decidualization via TLR4/NF-κB pathway inhibition. These findings highlight baicalein's potential as a therapeutic agent for URSA.

Tissue acidosis is a key characteristic of RA. It remains unclear whether acidosis promotes the formation of the complex adaptive immune landscape mainly characterized by T cell activation in RA by influencing synovial fibroblasts. This study aims to investigate the influence of acidosis on the immune microenvironment of RA by exploring the cytokine secretion and expression of co-stimulatory factors of RA synovial fibroblasts.

The Bulk RNA-seq dataset (GSE89408, Normal = 23, RA = 150) was utilized for cytokine screening and the immune state assessment based on disease stage. RNA-seq was employed to investigate cytokine and co-stimulatory molecule expression following 6 h of acid stimulation, combined with Bulk RNA-seq data to evaluate contributions to RA. Human cytokine arrays were used to confirm cytokine accumulation in supernatants after 12 h of acid stimulation. Proteomics was applied to explore cellular functional states in RASFs under 6 h of acid stress, with joint RNA-seq analysis elucidating transcription factor activation. Validation of select high-throughput data was performed using qRT-PCR and immune-based assays.

Bulk RNA-seq and RNA-seq identified 56 differentially expressed cytokines at their intersection. Functional enrichment analysis demonstrated that acid stimulation enhanced cytokine secretion and T cell chemotaxis in RA synovial fibroblasts (RASFs). Cytokine array revealed that acid exposure increased the accumulation of growth factors (e.g., FGF, VEGF) by over twofold and promoted the expression of multiple inflammatory and chemotactic factors. Immune state analysis indicated that acid stimulation induced a complex immune landscape by upregulating co-stimulatory and antigen-presenting molecules. Proteomics showed that acid stress enhanced mitochondrial function and triggered metabolic reprogramming in RASFs. Integrated transcriptomic and proteomic analyses revealed that AP1 regulates gene expression in RASFs, with its activation further confirmed by Western blotting and immunofluorescence.

FOXP3-expressing regulatory T (Treg) cells play a pivotal role in maintaining immune homeostasis and tolerance, with their activation being crucial for preventing various inflammatory responses. However, the mechanisms governing the epigenetic program in Treg cells during their dynamic activation remain unclear. In this study, we demonstrate that CXXC-finger protein 1 (CXXC1) interacts with the transcription factor FOXP3 and facilitates the regulation of target genes by modulating H3K4me3 deposition. Cxxc1 deletion in Treg cells leads to severe inflammatory disease and spontaneous T cell activation, with impaired immunosuppressive function. As a transcriptional regulator, CXXC1 promotes the expression of key Treg functional markers under steady-state conditions, which are essential for the maintenance of Treg cell homeostasis and their suppressive functions. Epigenetically, CXXC1 binds to the genomic regulatory regions of Treg program genes in mouse Treg cells, overlapping with FOXP3-binding sites. Given its critical role in Treg cell homeostasis, CXXC1 presents itself as a promising therapeutic target for autoimmune diseases.

The inflammatory microenvironment (IME) has been demonstrated to facilitate the initiation and progression of tumors throughout the inflammatory process. Simultaneously, cancer can initiate or intensify the inflammatory response, thereby promoting tumor progression. This review examines the dual role of long non-coding RNAs (lncRNAs) in the interplay between inflammation and cancer. LncRNA modulate inflammation-induced cancer by influencing the activation of signaling pathways (NF-κB, Wnt/β-catenin, mTOR, etc), microRNA (miRNA) sponging, protein interactions, interactions with immune cells, and encoding short peptides. In contrast, lncRNAs also impact cancer-induced inflammatory processes by regulating cytokine expression, mediating tumor-derived extracellular vesicles (EVs), modulating intracellular reactive oxygen species (ROS) levels, and facilitating metabolic reprogramming. Furthermore, the therapeutic potential of lncRNA and the challenges of clinical translation were explicitly discussed as well. Overall, this review aims to provide a comprehensive and systematic resource for future researchers investigating the impact of lncRNAs on inflammation and cancer.

Osteoimmunology is an emerging field that explores the interplay between bone and the immune system. The immune system plays a critical role in the pathogenesis of diabetes and significantly affects bone homeostasis. Artesunate, a first-line treatment for malaria, is known for its low toxicity and multifunctional properties. Increasing evidence suggests that artesunate possesses anti-inflammatory, immunoregulatory, and osteogenic effects. This review aims to explore the relationship between immune regulation and bone metabolism in type 2 diabetes (T2DM) and to investigate the potential therapeutic application of artesunate.

This review systematically examines literature from PubMed/Medline, Elsevier, Web of Science, Embase, the International Diabetes Federation, and other relevant databases.

This review synthesizes evidence from multiple sources to delineate the relationship between T lymphocytes and T2DM, the regulation of T lymphocyte subsets in bone metabolism, and the effects of artesunate on both T lymphocytes and bone metabolism. Recent studies suggest a bidirectional regulatory relationship between T2DM and T lymphocytes (CD4+ T and CD8+ T) during the onset and progression of the disease, with inflammatory and anti-inflammatory cytokines serving as key mediators. T lymphocyte subsets and their cytokines play a pivotal role in regulating osteogenesis and osteoclastogenesis in pathological conditions. Furthermore, artesunate has shown promise in modulating inflammatory infiltration and bone metabolism.

The accumulated evidence indicates that artesunate exerts regulatory effects on bone metabolism in T2DM by influencing T lymphocyte differentiation.

Nanomedicines for immune modulation have made advancements in the treatment of rheumatoid arthritis (RA). However, due to aberrations in patients' immune systems, inducing antigen-specific immune tolerance while halting disease progression remains a significant challenge. Here, we develop a highly targeted multifunctional nanocomplex, termed M2Exo@CuS-CitP-Rapa (M2CPR), with the aim of selectively inhibiting inflammatory immune reactions while promoting immune tolerance towards specific antigens. M2CPR specifically targets inflammatory tissues in RA, delivering CuS NPs, CitP, Rapa, and endogenous anti-inflammatory factors, thereby ameliorating the inflammatory joint microenvironment. CuS NPs induce Cuproptosis of activated T cells, whose fragments are engulfed by resident or recruited macrophages, resulting in abundant production of TGF-β. TGF-β acts synergistically with Rapa to induce the iDCs into tDCs. tDCs present CitP to Naive T cells, promoting Tregs differentiation. Tregs, in turn, produce more TGF-β, inducing tDCs differentiation, thereby establishing a cycle of immune tolerance. Through in vitro and in vivo experiments, we validate that M2CPR can induce robust and durable antigen-specific immune tolerance, offering a new paradigm for RA therapy.

Regulatory T cells (Tregs) play an important role in the immune system through the regulation of immunological self-tolerance and homeostasis. Furthermore, increasing evidence suggests the potential contribution of Tregs beyond immunity in the process of repairing various injured tissues. Tregs are generally characterised by the constitutive expression of forkhead box protein 3 (FOXP3) transcription factor in the nucleus and high expression levels of CD25 and CTLA-4 on the cell surface. To date, a large number of molecules have been identified as key regulators of Treg differentiation and function. Among these molecules are prostanoids, which are multifaceted lipid mediators. Prostanoids are produced from arachidonic acid through the catalytic activity of the enzyme cyclooxygenase and exert their functions through the 9 cognate receptors, DP1-2, EP1-EP4, FP, IP and TP. We briefly review previous studies on the regulatory mechanism of Tregs and then discuss recent works on the modulatory role of prostanoids.

N6-methyladenosine (m6A), a prevalent and essential RNA modification, serves a key function in driving autoimmune disease pathogenesis. By modulating immune cell development, activation, migration, and polarization, as well as inflammatory pathways, m6A is crucial in forming innate defenses and adaptive immunity. This article provides a comprehensive overview of m6A modification features and reveals how its dysregulation affects the intensity and persistence of immune responses, disrupts immune tolerance, exacerbates tissue damage, and promotes the development of autoimmunity. Specific examples include its contributions to systemic autoimmune disorders like lupus and rheumatoid arthritis, as well as conditions that targeting specific organs like multiple sclerosis and type 1 diabetes. Furthermore, this review explores the therapeutic promise of target m6A-related enzymes ("writers," "erasers," and "readers") and summarizes recent advances in intervention strategies. By focusing on the mechanistic and therapeutic implications of m6A modification, this review sheds light on its role as a promising tool for both diagnosis and treatment in autoimmune disorders, laying the foundation for advancements in customized medicine.

Primary Immune Thrombocytopenia (ITP) is characterized by reduced immunosuppressive function of regulatory T cells (Tregs), contributing to immune imbalance and decreased platelet counts. However, the mechanisms behind this reduced efficacy of Tregs remain unclear. Our study used a variety of methods, including Treg function assays, cytokine analysis, and single-cell sequencing, to explore these mechanisms. We found that exosomes from ITP patients inhibited TBX21 expression in Tregs, and impaired their ability to suppress Th1 cells. At the single-cell level, Tregs with high TBX21 expression were identified, and the activity of the TBX21 regulon was found to be enhanced in early-stage Treg subpopulations. We also discovered that ARID3A interacted with SPI1 and TBX21 gene regions, indicating a regulatory relationship between ARID3A, SPI1, and TBX21. Additionally, exosomes in ITP patients' plasma contained elevated levels of miR-363-3p, which negatively correlated with platelet count. These exosomes transferred miR-363-3p to Tregs, downregulating ARID3A, SPI1, and TBX21 expression, thereby weakening Tregs' ability to suppress conventional CD4 + T cells. In conclusion, exosomes from ITP patients reduced Treg function through the ARID3A/SPI1/TBX21 axis by miR-363-3p, diminishing their ability to regulate Th1 cells and contributing to the immune dysfunction observed in ITP.

Autoimmune uveitis (AU) is a severe intraocular autoimmune disorder with a chronic disease course and a high rate of blindness. Kurarinone (KU), a major component of the traditional Chinese medicine Sophorae Flavescentis Radix, possesses a wide spectrum of activities and has been used to treat several inflammation-related diseases.

We aimed to investigate the effects of KU on AU and its modulatory mechanisms.

We used an experimental autoimmune uveitis (EAU) animal model and characterized the comprehensive immune landscape of KU-treated EAU mice using single-cell RNA sequencing (scRNA-seq). The retina and lymph nodes were analyzed. The siRNAs and selective inhibitors were used to study the signaling pathway. The effect of KU on peripheral blood mononuclear cells (PBMCs) from uveitis patients was also examined.

We found that KU relieved chorioretinal lesions and immune cell infiltration in EAU model mice. Subsequent single-cell analysis revealed that KU downregulated the EAU-upregulated expression of inflammatory and autoimmune-related genes and suppressed pathways associated with immune cell differentiation, activation, and migration in a cell-specific manner. KU was implicated in restoring T helper 17 (Th17)/regulatory T (Treg) cell balance by alleviating inflammatory injury and elevating the expression of modulatory mediators in Tregs, while simultaneously ameliorating excessive inflammation by Th17 cells. Furthermore, Rac1 and the Id2/Pim1 axis potentiated the pathogenicity of Th17 cells during EAU, which was inhibited by KU treatment, contributing to the amelioration of EAU-induced inflammation and treatment of AU. In addition, KU suppressed inflammatory cytokine production in activated human PBMCs by inhibiting Rac1. Integration of the glucocorticoid-treated transcriptome suggests that KU has immunomodulatory effects on lymphocytes.

Our study constructed a high-resolution atlas of the immunoregulatory effects of KU treatment on EAU and identified its potential therapeutic mechanisms, which hold great promise in treating autoimmune disorders.

Plaque psoriasis (PP) is a chronic immune-mediated skin disorder with a genetic basis, characterized by abnormal T-cell responses. This study investigated the role of FOXP3 gene variants rs2280883 and rs3761548 in T-cell regulation through their effects on IL-10 and TGF-β1 cytokine levels and their association with PP risk. A case-control study was conducted, including 101 individuals with PP and 106 healthy controls from the Mexican population. Genotyping of FOXP3 variants was performed using PCR-RFLP, and cytokine levels were measured with ELISA kits. Significant differences in allele and genotype frequencies of the rs2280883 variant were observed between PP patients and controls, suggesting an association with an increased risk of PP. IL-10 levels were found to be elevated in PP patients, regardless of FOXP3 gene variants, indicating that cytokine dysregulation in PP may involve alternative pathways independent of FOXP3-mediated regulatory T-cell (Treg) function. No significant differences were detected in TGF-β1 levels or rs3761548 genotype frequencies across the study groups. In conclusion, the rs2280883 variant in the FOXP3 gene is significantly associated with a higher risk of developing PP in the Mexican population, while dysregulated IL-10 levels suggest a complex cytokine interaction beyond Treg activity.

The inclusion of immunomodulatory strategies as supportive therapies in ischemic heart disease (IHD) has garnered significant support over recent years. Several such approaches appear to be unified through their ultimate target, the NLRP3 inflammasome. This review presents a brief update on immunomodulatory strategies in the continuum of conditions constituting ischemic heart disease and emphasising on the seemingly unifying mechanism of NLRP3 activation as well as modulation across these conditions.

The NLRP3 inflammasome is a multiprotein complex assembled upon inflammatory stimulation, causing the release of pro-inflammatory cytokines and initiating pyroptosis. The NLRP3 pathway is relevant in inflammatory signalling of cardiac immune cells as well as non-immune cells in the myocardium, including cardiomyocytes, fibroblasts and endothelial cells. In addition to a focus on clinical outcome and efficacy trials of targeting NLRP3-related pathways, the potential connection between immunomodulation in cardiology and the NLRP3 pathway is currently being explored in preclinical trials. Colchicine, cytokine-based approaches and SGLT2 inhibitors have emerged as promising agents. However, the conditions comprising IHD including atherosclerosis, coronary artery disease (CAD), myocardial infarction (MI) and ischemic cardiomyopathy/heart failure (iCMP/HF) are not equally amenable to immunomodulation with the respective drugs. Atherosclerosis, coronary artery disease and ischemic cardiomyopathy are affected by chronic inflammation, but the immunomodulatory approach to acute inflammation in the post-MI setting remains a pharmacological challenge, as detrimental and regenerative effects of myocardial inflammation are initiated in unison. The NLRP3 inflammasome lies at the center of cell mediated inflammation in IHD. Recent trial evidence has highlighted anti-inflammatory effects of colchicine, interleukin-based therapy as well as SGLT2i in IHD and that the respective drugs modulate the NLRP3 inflammasome.

Recent oncological research has intensely focused on the tumor immune microenvironment (TME), particularly the functions of CD4 + T lymphocytes. CD4+ T lymphocytes have been implicated in antigen presentation, cytokine release, and cytotoxicity, suggesting their contribution to the dynamics of the TME. Furthermore, the application of single-cell sequencing has yielded profound insights into the phenotypic diversity and functional specificity of CD4+ T cells in the TME. In this review, we discuss the current findings from single-cell analyses, emphasizing the heterogeneity of CD4+ T cell subsets and their implications in tumor immunology. In addition, we review the critical signaling pathways and molecular networks underpinning CD4+ T cell activities, thereby offering novel perspectives on therapeutic targets and strategies for cancer treatment and prognosis.

Recent evidence has highlighted the functions of enhancers in modulating transcriptional machinery and affecting the development of human diseases including rheumatoid arthritis (RA). Enhancer RNAs (eRNAs) are RNA molecules transcribed from active enhancer regions. This study investigates the specific function of eRNA in gene transcription and osteoclastogenesis in RA. Regulator of G protein signaling 1 (RGS1)-associated eRNA was highly activated in osteoclasts according to bioinformatics prediction. RGS1 mRNA was increased in mice with collagen-induced arthritis as well as in M-CSF/soluble RANKL-stimulated macrophages (derived from monocytes). This was ascribed to increased RGS1 eRNA activity. Silencing of 5'-eRNA blocked the binding between forkhead box J3 (FOXJ3) and the RGS1 promoter, thus suppressing RGS1 transcription. RGS1 accelerated osteoclastogenesis through PLC-IP3R-dependent Ca2+ response. Knockdown of either FOXJ3 or RGS1 ameliorated arthritis severity, improved pathological changes, and reduced osteoclastogenesis and bone erosion in vivo and in vitro. However, the effects of FOXJ3 silencing were negated by RGS1 overexpression. In conclusion, this study demonstrates that the RGS1 eRNA-driven transcriptional activation of the FOXJ3/RGS1 axis accelerates osteoclastogenesis through PLC-IP3R dependent Ca2+ response in RA. The finding may offer novel insights into the role of eRNA in gene transcription and osteoclastogenesis in RA.

Regulatory T (Treg) cells are essential for maintaining immune homeostasis by suppressing excessive immune responses. In the context of cancer, however, Tregs promote immune evasion and tumor progression, particularly through their unique adaptations within the tumor microenvironment (TME). Recent research has emphasized how metabolic characteristics shape Treg activation, migration, and immunosuppressive function, revealing the impact of metabolic pathways on Treg fitness in homeostasis and within the TME. In this review, we first provide an overview of Tregs in cancer immunology, discussing their immunosuppressive roles and properties specific to the TME. We then examine the metabolic requirements for Treg activation and migration under normal conditions, followed by a discussion of how hypoxia, lactate accumulation, nutrient limitation, oxidative stress, and other TME-specific factors alter Treg metabolism and contribute to cancer immune evasion. Finally, we explore therapeutic strategies that target Treg metabolism within the TME, including pharmacological modulation of specific metabolic pathways to diminish Treg-mediated immunosuppression. Thus, we could suggest future directions and clinical implications for Treg-targeted metabolic modulation as a complementary approach in cancer treatment, setting the stage for novel strategies in immunotherapy.

Moyamoya disease (MMD) is a rare progressive cerebrovascular disorder characterized by the stenosis or occlusion of the terminal segments of the internal carotid arteries, leading to the development of abnormal collateral vascular networks. These networks are a compensatory mechanism for reduced blood flow to the brain. Despite extensive research, the exact etiology of MMD remains unknown, although recent studies suggest that immune system dysfunction plays a critical role in its pathogenesis. In particular, the involvement of immune cells such as T cells, macrophages, and dendritic cells has been increasingly recognized. These immune cells contribute to the inflammatory process and vascular remodeling observed in MMD patients, further complicating the disease's progression. Inflammation and immune-mediated damage to the vessel walls may accelerate the narrowing and occlusion of arteries, exacerbating ischemic events in the brain. Additionally, studies have revealed that certain genetic and environmental factors can influence immune system activation in MMD, linking these pathways to disease development. This review aims to provide a comprehensive overview of the immune mechanisms at play in MMD, focusing on how immune cells participate in vascular injury and remodeling. Understanding these immunological processes may offer new therapeutic targets to halt or reverse disease progression, potentially leading to more effective treatment strategies for MMD.

In recent years, epigenetic modifications have attracted significant attention due to their unique regulatory mechanisms and profound biological implications. Acting as a bridge between environmental stimuli and changes in gene activity, they reshape gene expression patterns, providing organisms with regulatory mechanisms to respond to environmental changes. A growing body of evidence indicates that epigenetic regulation plays a crucial role in the pathogenesis and progression of psoriasis. A deeper understanding of these epigenetic mechanisms not only helps unveil the molecular mechanisms underlying the initiation and progression of psoriasis but may also provide new insights into diagnostic and therapeutic strategies. Given the unique roles and significant contributions of various cell types involved in the process of psoriasis, a thorough analysis of specific epigenetic patterns in different cell types becomes a key entry point for elucidating the mechanisms of disease development. Although epigenetic modifications encompass multiple complex layers, this review will focus on histone modifications and DNA methylation, describing how they function in different cell types and subsequently impact the pathophysiological processes of psoriasis. Finally, we will summarize the current problems in research concerning histone modifications and DNA methylation in psoriasis and discuss the clinical application prospects and challenges of targeting epigenetic modifications as therapeutic strategies for psoriasis.

Regulatory T cells (Tregs) have been shown to be involved in the induction of transplantation tolerance in numerous models. Our previous work demonstrated that methyltransferase-like 14 (METTL14) loss impaired Treg function and hindered the establishment of transplantation tolerance. However, the underlying mechanisms remain unclear. In this study, we found that METTL14 knockdown in Tregs significantly impaired their regulatory function, leading to poor allograft function and accelerated transplant rejection. Using methylated RNA immunoprecipitation- and mRNA-sequencing approaches, we discovered that METTL14 deficiency fostered the expression of semaphorin 4D (Sema4D) mRNA, a key semaphorin family member with immunoregulatory activity. Methylation of target adenosines reduced Sema4D mRNA degradation, a process mediated by the METTL14-YTH N6-methyladenosine RNA binding protein 2 axis. Inhibition of Sema4D suppressed its interaction with its receptor, thereby preserving Treg immunoregulation capability and prolonging allograft survival through the p21-activated kinase-signal transducer and activator of transcription 5signaling pathway. Importantly, Sema4D expression in kidney transplant biopsies were negatively correlated with renal allograft survival. In summary, our findings suggest that METTL14 deficiency in Tregs leads to transplant rejection and reveal for the first time that Sema4D may serve as a potential therapeutic target to enhance Treg function in transplantation.

Septic arthritis (SA) caused by Staphylococcus aureus is a severe inflammatory joint disease, characterized by synovitis accompanied with cartilage destruction and bone erosion. The available antibiotic treatment alone is insufficient to resolve the inflammation that leads to high rates of morbidity and mortality. Among the CD4+ T helper lymphocytes, the Th17 and Tregs are key regulators of immune homeostasis. A high Th17 could lead to autoimmunity, whereas an increase in Tregs indicates immunosuppression. Depending on the external cytokine milieu, naïve CD4+ T cells transform into either Th17 or Treg cell lineage. TGF-β in the presence of IL-21 produces Th17 cells and drives the inflammatory cascade of reactions. We studied the effects of in vivo neutralization of TGF-β and IL-21 in septic arthritic mice to control arthritic inflammation, which has not been studied before. The arthritic index showed maximum severity in the SA group which substantially reduced in the Ab-treated groups. Flow cytometric analyses of peripheral blood collected from mice at 9DPI revealed the highest Th17/Treg ratio in the SA group but least in the combined-antibody-treated group. TGF-β1 and IL-21 cytokine production from serum, spleen, and synovial tissue homogenates was significantly reduced in the dual Ab-treated group than in the untreated SA group. From the Western blot analyses obtained from splenic lymphocytes at 9 DPI, we elucidated the possible underlying mechanism of interplay in downstream signalling involving the interaction between different STAT proteins and SOCS, NF-κB, RANKL, mTOR, iNOS, and COX-2 in regulating inflammation and osteoclastogenesis. On endogenous blockade with TGF-β and IL-21, the Th17/Treg ratio and resultant arthritic inflammation in SA were found to be reduced. Therefore, maintaining the Th17/Treg balance is critical to eradicate infection as well as suppress excessive inflammation and neutralization of TGF-β and IL-21 could provide a novel therapeutic strategy to treat staphylococcal SA.

The ability of cells to maintain distinct identities and respond to transient environmental signals requires tightly controlled regulation of gene networks1-3. These dynamic regulatory circuits that respond to extracellular cues in primary human cells remain poorly defined. The need for context-dependent regulation is prominent in T cells, where distinct lineages must respond to diverse signals to mount effective immune responses and maintain homeostasis4-8. Here we performed CRISPR screens in multiple primary human CD4+ T cell contexts to identify regulators that control expression of IL-2Rα, a canonical marker of T cell activation transiently expressed by pro-inflammatory effector T cells and constitutively expressed by anti-inflammatory regulatory T cells where it is required for fitness9-11. Approximately 90% of identified regulators of IL-2Rα had effects that varied across cell types and/or stimulation states, including a subset that even had opposite effects across conditions. Using single-cell transcriptomics after pooled perturbation of context-specific screen hits, we characterized specific factors as regulators of overall rest or activation and constructed state-specific regulatory networks. MED12 - a component of the Mediator complex - serves as a dynamic orchestrator of key regulators, controlling expression of distinct sets of regulators in different T cell contexts. Immunoprecipitation-mass spectrometry revealed that MED12 interacts with the histone methylating COMPASS complex. MED12 was required for histone methylation and expression of genes encoding key context-specific regulators, including the rest maintenance factor KLF2 and the versatile regulator MYC. CRISPR ablation of MED12 blunted the cell-state transitions between rest and activation and protected from activation-induced cell death. Overall, this work leverages CRISPR screens performed across conditions to define dynamic gene circuits required to establish resting and activated T cell states.

This study aims to examine the alterations and clinical significance of CD8+ regulatory T cell subsets in the peripheral blood of individuals with type 1 diabetes mellitus (T1DM).

From January 2020 to December 2023, a study was conducted involving 40 individuals with T1DM, who visited the Department of Endocrinology at the First Affiliated Hospital of Nanjing Medical University (T1DM group). For comparison, 40 healthy individuals who underwent routine physical examinations at the same hospital during this period were selected as the control group. Peripheral blood mononuclear cells were isolated, and CD8+ T cells were labeled with CD3, CD25 and FoxP3 to analyze their subset frequencies using flow cytometry. The study examined differences in subset frequencies between the two groups and explored correlations between subset frequency, disease duration, and age of onset.

The frequencies of CD8+ CD25+, CD8+ FoxP3+, CD8+ CD25+ CD3+ and CD8+ FoxP3+ CD3+ subsets in peripheral blood mononuclear cells did not significantly differ between the healthy control group and the T1DM group (P > 0.05). In the T1DM group, the expression level of CD25 on CD8+ T cells showed no correlation with the age of onset or disease duration, and FoxP3 levels were also unrelated to the age of onset, with no statistical differences (P > 0.05). However, within the T1DM group, FoxP3 levels progressively decreased with longer disease duration, demonstrating a statistically significant negative correlation (Pearson r = -0.331, P < 0.05). In the T1DM group, the level of CD3+ CD8+ T cells expressed CD25, and there was no correlation between Foxp 3 level and age of onset, not statistically significant (P > 0.05), but the level of Foxp 3 in the T1DM group decreased with the duration of the disease, (Pearson r= - 0.363, P < 0.05).

The levels of CD8+FoxP3+ regulatory T cells in peripheral blood mononuclear cells of patients with T1DM show a significant correlation with disease duration, suggesting that these cells may play a critical role in the progression of T1DM.

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.

Sepsis is a disease associated with high morbidity and mortality rates, especially among the elderly and patients in intensive care units. Disulfidptosis, a newly identified form of cell death triggered by disulfide stress, is emerging as a significant factor in disease progression. This study aimed to explore the diagnostic and prognostic value of disulfidptosis-related genes in sepsis.

We obtained two datasets from the Gene Expression Omnibus (GEO) database to conduct our analysis. Functional enrichment analysis was performed to identify relevant biological pathways. A protein-protein interaction network was constructed to identify hub genes critical to sepsis. Additionally, we analyzed the immune infiltration status in sepsis patients. The diagnostic value of these hub genes for sepsis was evaluated using nomograms, receiver operating characteristic (ROC) curves, and calibration curves in both training and validation datasets. Finally, a miRNA-immune-related hub genes (miRNA-IHGs) regulatory network was developed to elucidate the synergistic interactions between miRNAs and their target genes.

A total of 3,469 differentially expressed genes (DEGs) were identified, of which seven were related to disulfidptosis (DR-DEGs). Functional enrichment analysis showed that DR-DEGs were significantly enriched in pathways related to actin dynamics. Five hub genes (MYH10, ACTN4, MYH9, FLNA, and IQGAP1) were identified as central to these processes. The analysis of immune infiltration revealed significantly lower levels of 11 immune cell types, while macrophages and regulatory T cells were significantly elevated in sepsis patients. The area under the ROC curves (AUCs) of the IHGs risk prediction model were 0.917 and 0.894 for the training and validation sets, respectively. A miRNA-IHGs regulatory network, comprising 17 nodes and 27 edges, was constructed, with MYH9 being the most frequently regulated by miRNAs.

The pathophysiological process of sepsis appears to involve disulfidptosis, highlighting it as a potential new therapeutic targets for sepsis management.

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants that have been linked to a number of health outcomes, including those related to immune dysfunction. However, there are limited numbers of epidemiological-based studies that directly examine the association between PFAS exposure and immune responses.

In this cross-sectional study nested in the California Teachers Study cohort, we measured nine PFAS analytes in serum. Of the 9 analytes, we further evaluated four (PFHxS [perfluorohexane sulfonate], PFNA [perfluorononanoic acid], PFOA [perfluorooctanoic acid], PFOS [perfluorooctanesulfonic acid]) that had detection levels of > 80 %, in relation to 16 systemic inflammatory/immune markers and corresponding immune pathways (Th1 [pro-inflammatory/macrophage activation], B-cell activation, and T-cell activation). Study participants (n = 722) were female, completed a questionnaire regarding various health measures and behaviors, and donated a blood sample between 2013-2016. The association between PFAS analytes and individual immune markers and pathways were evaluated by calculating odds ratios (OR) and 95 % confidence intervals (CI) in a logistic regression model. PFAS analytes were evaluated both as a dichotomous exposure (above or below the respective median) and as a continuous variable (per 1 unit increase [ng/mL]).

The prevalence of detecting any PFAS analyte rose with increasing age, with the highest PFAS prevalence observed among those aged 75 + years and the lowest PFAS prevalence observed among those aged 40-49 years (study participant age range: 40-95 years). Significant associations with BAFF (B-cell activating factor) levels above the median were observed among participants with elevated (defined as above the median) levels of PFHxS (OR=1.53), PFOA (OR=1.43), and PFOS (OR=1.40). Similarly, there were statistically significant associations between elevated levels of PFHxS and TNFRII (tumor necrosis factor receptor 2) levels (OR=1.78) and IL2Rα (interleukin 2 receptor subunit alpha) levels (OR=1.48). We also observed significant inverse associations between elevated PFNA and sCD14 (soluble cluster of differentiation 14) (OR=0.73). No significant associations were observed between elevated PFNA and any immune marker. Evaluation of PFAS exposures as continuous exposures in association with dichotomized cytokines were generally consistent with the dichotomized associations.

PFAS exposure was associated with altered levels of circulating inflammatory/immune markers; the associations were specific to PFAS analyte and immune marker. If validated, our results may suggest potential immune mechanisms underlying associations between the different PFAS analytes and adverse health outcomes.

Ischemic heart disease (IHD) is a prevalent cardiovascular condition that remains the primary cause of death due to its adverse ventricular remodelling and pathological changes in end-stage heart failure. As a complex pathologic condition, it involves intricate regulatory processes at the cellular and molecular levels. The immune system and cardiovascular system are closely interconnected, with immune cells playing a crucial role in maintaining cardiac health and influencing disease progression. Consequently, alterations in the cardiac microenvironment are influenced and controlled by various immune cells, such as macrophages, neutrophils, dendritic cells, eosinophils, and T-lymphocytes, along with the cytokines they produce. Furthermore, studies have revealed that Gata6+ pericardial cavity macrophages play a key role in regulating immune cell migration and subsequent myocardial tissue repair post IHD onset. This review outlines the role of immune cells in orchestrating inflammatory responses and facilitating myocardial repair following IHD, considering both macro and micro views. It also discusses innovative immune cell-based therapeutic strategies, offering new insights for further research on the pathophysiology of ischemic heart disease and immune cell-targeted therapy for IHD.

Our study aimed to investigate whether BMSCs-derived exosomal miR-381 promotes Treg cell differentiation in lung ischemia-reperfusion injury (LIRI), and the underlying mechanism.

The in vitro and in vivo models of LIRI were established by hypoxia/reoxygenation (H/R) treatment and lung ischemia/reperfusion (I/R) surgery, respectively. BMSCs-derived exosomes were isolated and identified by western blot, nanoparticle tracking analysis, and transmission electron microscopy. Cell viability, proliferation, and apoptosis were assessed by CCK-8, EdU, and flow cytometry assay, respectively. IL-18 secretion level in lung microvascular endothelial cells (LMECs) and lung tissue homogenate was examined by ELISA. Treg cell differentiation was determined using flow cytometry. The relationships between miR-381, YTHDF1, and IL-18 were investigated using dual-luciferase reporter gene, RIP, and/or RNA pull-down assays. MeRIP assay was employed to determine m6A modification of IL-18 mRNA in LMECs. The ubiquitination level of Foxp3 protein in CD4+ T cells was analyzed by Co-IP assay.

BMSCs-derived exosomes reduced LMECs injury and increased Treg cell differentiation in LIRI, whereas miR-381 inhibition in BMSCs weakened these impacts. Mechanistically, miR-381 inhibited IL-18 translation in LMECs by inhibiting YTHDF1 expression via binding to its 3'-UTR. As expected, YTHDF1 overexpression in LMECs abolished the effects of miR-381-overexpressed exosomes on LMECs injury and Treg cell differentiation. Moreover, LMECs-secreted IL-18 inhibited Treg cell differentiation by promoting the ubiquitination degradation of Foxp3 protein.

BMSCs-derived exosomal miR-381 suppressed IL-18 translation in LMECs through binding to YTHDF1 3'-UTR, thus suppressing the ubiquitination degradation of Foxp3 in CD4+ T cells, which promoted Treg cell differentiation and mitigated LIRI development.

Graves' disease (GD) is an autoimmune condition that can progress to Graves' ophthalmopathy (GO), leading to irreversible damage to orbital tissues and potential blindness. The pathogenic mechanism is not fully understood. In this study, we conducted single-cell multi-omics analyses on healthy individuals, patients with GD without GO, newly diagnosed patients with GO, and treated patients with GO. Our findings revealed gradual systemic inflammation during GO progression, marked by overactivation of cytotoxic effector T cell subsets, and expansion of specific T cell receptor clones. Importantly, we observed a decline in the immunosuppressive function of activated Treg (aTreg) accompanied by a cytotoxic phenotypic transition. In vitro experiments revealed that dysfunction and transition of GO-autoreactive Treg were regulated by the yin yang 1 (YY1) upon secondary stimulation of thyroid stimulating hormone receptor (TSHR) under inflammatory conditions. Furthermore, adoptive transfer experiments of the GO mouse model confirmed infiltration of these cytotoxic Treg into the orbital lesion tissues. Notably, these cells were found to upregulate inflammation and promote pathogenic fibrosis of orbital fibroblasts (OFs). Our results reveal the dynamic changes in immune landscape during GO progression and provide direct insights into the instability and phenotypic transition of Treg, offering potential targets for therapeutic intervention and prevention of autoimmune diseases.

Sepsis can induce sepsis-associated encephalopathy (SAE), with Ulinastatin (UTI) serving a critical anti-inflammatory role. This study aimed to identify the hub genes in an SAE mouse model following UTI intervention and investigate the underlying molecular mechanisms.

Through differential expression analysis to obtain differentially expressed genes (DEGs), ie, UTI vs CLP (DEGs1) and Con vs CLP (DEGs2). After taking the intersection of the genes with opposite differential trends in these two parts and immune-related genes (IRGs), DE-IRGs were obtained. Hub genes in the protein-protein interaction (PPI) network were then determined using six algorithms from the Cytohubba plugin in Cytoscape. Gene set enrichment analysis (GSEA) was employed to explore the functional relevance of these hub genes. Additionally, the immune microenvironment across the three groups was compared, and hub gene-related drugs were predicted using an online database. Finally, qRT-PCR was used to validate the expression of the hub genes in hippocampal tissue from CLP mice.

RNA sequencing obtained 864 differentially expressed genes (DEGs) (CLP vs Con) and 279 DEGs (UTI vs CLP). Taking the intersection of DEGs with opposite expression trends yielded 165 DEGs. Six key genes (ICAM - 1, IRF7, IL - 1β, CCL2, IL - 6 and SOCS3) were screened by six algorithms. Immune infiltration analysis found that Treg cells were reversed after treatment with UTI in the diseased state. A total of 106 hub - gene - related drugs were predicted, among which BINDARIT - CCL2 and LIFITEGRAST - ICAM1 showed particularly high affinities. The qRT - PCR verification results were consistent with the sequencing results.

In conclusion, ICAM-1, IRF7, IL-1β, CCL2, IL-6, and SOCS3 were identified as potential therapeutic targets in SAE mice treated with UTI. This study offers theoretical support for UTI as a treatment option for SAE.

Autoimmune diseases comprise a large group of conditions characterized by a complex pathogenesis and significant heterogeneity in their clinical manifestations. Advances in sequencing technology have revealed that in addition to genetic susceptibility, various epigenetic mechanisms including DNA methylation and histone modification play critical roles in disease development. The emerging field of epigenetics has provided new perspectives on the pathogenesis and development of autoimmune diseases. Aberrant epigenetic modifications can be used as biomarkers for disease diagnosis and prognosis. Exploration of human epigenetic profiles revealed that patients with autoimmune diseases exhibit markedly altered DNA methylation profiles compared with healthy individuals. Targeted cutting-edge epigenetic therapies are emerging. For example, DNA methylation inhibitors can rectify methylation dysregulation and relieve patients. Histone deacetylase inhibitors such as vorinostat can affect chromatin accessibility and further regulate gene expression, and have been used in treating hematological malignancies. Epigenetic therapies have opened new avenues for the precise treatment of autoimmune diseases and offer new opportunities for improved therapeutic outcomes. Our review can aid in comprehensively elucidation of the mechanisms of autoimmune diseases and development of new targeted therapies that ultimately benefit patients with these conditions.