MicroRNA-19b exacerbates systemic sclerosis through promoting Th9 cells.

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and multiple vital organs, but the immunological pathogenesis of SSc remains unclear. We show here that miR-19b promotes Th9 cells that exacerbate SSc. Specifically, miR-19b and interleukin (IL)-9 increase in CD4+ T cells in experimental SSc in mice induced with bleomycin. Inhibiting miR-19b reduces Th9 cells and ameliorates the disease. Mechanistically, transforming growth factor beta (TGF-ß) plus IL-4 activates pSmad3-Ser213 and TRAF6-K63 ubiquitination by suppressing NLRC3. Activated TRAF6 sequentially promotes TGF-ß-activated kinase 1 (TAK1) and nuclear factor κB (NF-κB) p65 phosphorylation, leading to the upregulation of miR-19b. Notably, miR-19b activated Il9 gene expression by directly suppressing atypical E2F family member E2f8. In patients with SSc, higher levels of IL9 and MIR-19B correlate with worse disease progression. Our findings reveal miR-19b as a key factor in Th9 cell-mediated SSc pathogenesis and should have clinical implications for patients with SSc.

CPT-11 mitigates autoimmune diseases by suppressing effector T cells without affecting long-term anti-tumor immunity.

The incidence of autoimmune diseases has significantly increased over the past 20 years. Excessive host immunoreactions and disordered immunoregulation are at the core of the pathogenesis of autoimmune diseases. The traditional anti-tumor chemotherapy drug CPT-11 is associated with leukopenia. Considering that CPT-11 induces leukopenia, we believe that it is a promising drug for the control of autoimmune diseases. Here, we show that CPT-11 suppresses T cell proliferation and pro-inflammatory cytokine production in healthy C57BL/6 mice and in complete Freund's adjuvant-challenged mice. We found that CPT-11 effectively inhibited T cell proliferation and Th1 and Th17 cell differentiation by inhibiting glycolysis in T cells. We also assessed CPT-11 efficacy in treating autoimmune diseases in models of experimental autoimmune encephalomyelitis and psoriasis. Finally, we proved that treatment of autoimmune diseases with CPT-11 did not suppress long-term immune surveillance for cancer. Taken together, these results show that CPT-11 is a promising immunosuppressive drug for autoimmune disease treatment.

TSG-6 Inhibits the NF-κB Signaling Pathway and Promotes the Odontogenic Differentiation of Dental Pulp Stem Cells via CD44 in an Inflammatory Environment.

In pulpitis, dentinal restorative processes are considerably associated with undifferentiated mesenchymal cells in the pulp. This study aimed to investigate strategies to improve the odonto/osteogenic differentiation of dental pulp stem cells (DPSCs) in an inflammatory environment. After pretreatment of DPSCs with 20 ng/mL tumor necrosis factor-induced protein-6 (TSG-6), DPSCs were cultured in an inflammation-inducing solution. Real-time polymerase chain reaction and Western blotting were performed to measure the expression levels of nuclear factor kappa B (NF-κB) and odonto/osteogenic differentiation markers, respectively. Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays were used to assess cell proliferation and activity. Subcutaneous ectopic osteogenesis and mandibular bone cultures were performed to assess the effects of TSG-6 in vivo. The expression levels of odonto/osteogenic markers were higher in TSG-6-pre-treated DPSCs than nontreated DPSCs, whereas NF-κB-related proteins were lower after the induction of inflammation. An anti-CD44 antibody counteracted the rescue effect of TSG-6 on DPSC activity and mineralization in an inflammatory environment. Exogenous administration of TSG-6 enhanced the anti-inflammatory properties of DPSCs and partially restored their mineralization function by inhibiting NF-κB signaling. The mechanism of action of TSG-6 was attributed to its interaction with CD44. These findings reveal novel mechanisms by which DPSCs counter inflammation and provide a basis for the treatment of pulpitis.

Interactions between neutrophils and T-helper 17 cells.

Neutrophils comprise the majority of immune cells in human peripheral circulation, have potent antimicrobial activities, and are clinically significant in their abundance, heterogeneity, and subcellular localization. In the past few years, the role of neutrophils as components of the innate immune response has been studied in numerous ways, and these cells are crucial in fighting infections, autoimmune diseases, and cancer. T-helper 17 (Th17) cells that produce interleukin 17 (IL-17) are critical in fighting infections and maintaining mucosal immune homeostasis, whereas they mediate several autoimmune diseases. Neutrophils affect adaptive immune responses by interacting with adaptive immune cells. In this review, we describe the physiological roles of both Th17 cells and neutrophils and their interactions and briefly describe the pathological processes in which these two cell types participate. We provide a summary of relevant drugs targeting IL-17A and their clinical trials. Here, we highlight the interactions between Th17 cells and neutrophils in diverse pathophysiological situations.

Reactive oxygen species formation and its effect on CD4+ T cell-mediated inflammation.

Reactive oxygen species (ROS) are produced both enzymatically and non-enzymatically in vivo. Physiological concentrations of ROS act as signaling molecules that participate in various physiological and pathophysiological activities and play an important role in basic metabolic functions. Diseases related to metabolic disorders may be affected by changes in redox balance. This review details the common generation pathways of intracellular ROS and discusses the damage to physiological functions when the ROS concentration is too high to reach an oxidative stress state. We also summarize the main features and energy metabolism of CD4+ T-cell activation and differentiation and the effects of ROS produced during the oxidative metabolism of CD4+ T cells. Because the current treatment for autoimmune diseases damages other immune responses and functional cells in the body, inhibiting the activation and differentiation of autoreactive T cells by targeting oxidative metabolism or ROS production without damaging systemic immune function is a promising treatment option. Therefore, exploring the relationship between T-cell energy metabolism and ROS and the T-cell differentiation process provides theoretical support for discovering effective treatments for T cell-mediated autoimmune diseases.

Signaling pathways involved in the biological functions of dendritic cells and their implications for disease treatment.

The ability of dendritic cells (DCs) to initiate and regulate adaptive immune responses is fundamental for maintaining immune homeostasis upon exposure to self or foreign antigens. The immune regulatory function of DCs is strictly controlled by their distribution as well as by cytokines, chemokines, and transcriptional programming. These factors work in conjunction to determine whether DCs exert an immunosuppressive or immune-activating function. Therefore, understanding the molecular signals involved in DC-dependent immunoregulation is crucial in providing insight into the generation of organismal immunity and revealing potential clinical applications of DCs. Considering the many breakthroughs in DC research in recent years, in this review we focused on three basic lines of research directly related to the biological functions of DCs and summarized new immunotherapeutic strategies involving DCs. First, we reviewed recent findings on DC subsets and identified lineage-restricted transcription factors that guide the development of different DC subsets. Second, we discussed the recognition and processing of antigens by DCs through pattern recognition receptors, endogenous/exogenous pathways, and the presentation of antigens through peptide/major histocompatibility complexes. Third, we reviewed how interactions between DCs and T cells coordinate immune homeostasis in vivo via multiple pathways. Finally, we summarized the application of DC-based immunotherapy for autoimmune diseases and tumors and highlighted potential research prospects for immunotherapy that targets DCs. This review provides a useful resource to better understand the immunomodulatory signals involved in different subsets of DCs and the manipulation of these immune signals can facilitate DC-based immunotherapy.

TGF-ß controls development of TCRγδ+CD8αα+ intestinal intraepithelial lymphocytes.

γδ intestinal intraepithelial lymphocytes (IELs) constitute the majority of IELs with unique CD8αα+ homodimers that are distinct from γδT cells in other tissues. However, it remains largely unclear how those cells develop. Here we show that transforming growth factor beta (TGF-ß) signaling controls the development of TCRγδ+CD8αα+ IELs. Deletion of TGF-ß receptors or Smad3 and Smad2 in bone marrow stem cells caused a deficiency of TCRγδ+CD8αα+ IELs in mixed bone marrow chimeric mice. Mechanistically, TGF-ß is required for the development of TCRγδ+CD8αα+ IELs thymic precursors (CD44-CD25- γδ thymocytes). In addition, TGF-ß signaling induced CD8α in thymic γδT cells and maintained CD8α expression and survival in TCRγδ+CD8αα+ IELs. Moreover, TGF-ß also indirectly controls TCRγδ+CD8αα+ IELs by modulating the function of intestinal epithelial cells (IECs). Importantly, TGF-ß signaling in TCRγδ+CD8αα+ IELs safeguarded the integrity of the intestinal barrier in dextran sulfate sodium (DSS)-induced colitis.

Single-cell immune profiling reveals immune responses in oral lichen planus.

Introduction: Oral lichen planus (OLP) is a common chronic inflammatory disorder of the oral mucosa with an unclear etiology. Several types of immune cells are involved in the pathogenesis of OLP. Methods: We used single-cell RNA sequencing and immune repertoire sequencing to characterize the mucosal immune microenvironment of OLP. The presence of tissue-resident memory CD8+ T cells are validated by multiplex immunofluorescence. Results: We generated a transcriptome atlas from four OLP biopsy samples and their paired peripheral blood mononuclear cells (PBMCs), and compared them with two healthy tissues and three healthy PBMCs samples. Our analysis revealed activated tissue-resident memory CD8+ T cells in OLP tissues. T cell receptor repertoires displayed apperant clonal expansion and preferrential gene pairing in OLP patients. Additionally, obvious BCR clonal expansion was observed in OLP lesions. Plasmacytoid dendritic cells, a subtype that can promote dendritic cell maturation and enhance lymphocyte cytotoxicity, were identified in OLP. Conventional dendritic cells and macrophages are also found to exhibit pro-inflammatory activity in OLP. Cell-cell communication analysis reveals that fibroblasts might promote the recruitment and extravasation of immune cells into connective tissue. Discussion: Our study provides insights into the immune ecosystem of OLP, serving as a valuable resource for precision diagnosis and therapy of OLP.

Pathogenesis and treatment of Sjogren's syndrome: Review and update.

Sjogren's syndrome (SS) is a chronic autoimmune disease accompanied by multiple lesions. The main manifestations include dryness of the mouth and eyes, along with systemic complications (e.g., pulmonary disease, kidney injury, and lymphoma). In this review, we highlight that IFNs, Th17 cell-related cytokines (IL-17 and IL-23), and B cell-related cytokines (TNF and BAFF) are crucial for the pathogenesis of SS. We also summarize the advances in experimental treatment strategies, including targeting Treg/Th17, mesenchymal stem cell treatment, targeting BAFF, inhibiting JAK pathway, et al. Similar to that of SLE, RA, and MS, biotherapeutic strategies of SS consist of neutralizing antibodies and inflammation-related receptor blockers targeting proinflammatory signaling pathways. However, clinical research on SS therapy is comparatively rare. Moreover, the differences in the curative effects of immunotherapies among SS and other autoimmune diseases are not fully understood. We emphasize that targeted drugs, low-side-effect drugs, and combination therapies should be the focus of future research.

Development and function of natural TCR+ CD8αα+ intraepithelial lymphocytes.

The complexity of intestinal homeostasis results from the ability of the intestinal epithelium to absorb nutrients, harbor multiple external and internal antigens, and accommodate diverse immune cells. Intestinal intraepithelial lymphocytes (IELs) are a unique cell population embedded within the intestinal epithelial layer, contributing to the formation of the mucosal epithelial barrier and serving as a first-line defense against microbial invasion. TCRαß+ CD4- CD8αα+ CD8αß- and TCRγδ+ CD4- CD8αα+ CD8αß- IELs are the two predominant subsets of natural IELs. These cells play an essential role in various intestinal diseases, such as infections and inflammatory diseases, and act as immune regulators in the gut. However, their developmental and functional patterns are extremely distinct, and the mechanisms underlying their development and migration to the intestine are not fully understood. One example is that Bcl-2 promotes the survival of thymic precursors of IELs. Mature TCRαß+ CD4- CD8αα+ CD8αß- IELs seem to be involved in immune regulation, while TCRγδ+ CD4- CD8αα+ CD8αß- IELs might be involved in immune surveillance by promoting homeostasis of host microbiota, protecting and restoring the integrity of mucosal epithelium, inhibiting microbiota invasion, and limiting excessive inflammation. In this review, we elucidated and organized effectively the functions and development of these cells to guide future studies in this field. We also discussed key scientific questions that need to be addressed in this area.

Opposing functions of circadian protein DBP and atypical E2F family E2F8 in anti-tumor Th9 cell differentiation.

Interleukin-9 (IL-9)-producing CD4+ T helper cells (Th9) have been implicated in allergy/asthma and anti-tumor immunity, yet molecular insights on their differentiation from activated T cells, driven by IL-4 and transforming growth factor-beta (TGF-ß), is still lacking. Here we show opposing functions of two transcription factors, D-binding protein (DBP) and E2F8, in controlling Th9 differentiation. Specifically, TGF-ß and IL-4 signaling induces phosphorylation of the serine 213 site in the linker region of the Smad3 (pSmad3L-Ser213) via phosphorylated p38, which is necessary and sufficient for Il9 gene transcription. We identify DBP and E2F8 as an activator and repressor, respectively, for Il9 transcription by pSmad3L-Ser213. Notably, Th9 cells with siRNA-mediated knockdown for Dbp or E2f8 promote and suppress tumor growth, respectively, in mouse tumor models. Importantly, DBP and E2F8 also exhibit opposing functions in regulating human TH9 differentiation in vitro. Thus, our data uncover a molecular mechanism of Smad3 linker region-mediated, opposing functions of DBP and E2F8 in Th9 differentiation.

Excessive intake of sugar: An accomplice of inflammation.

High sugar intake has long been recognized as a potential environmental risk factor for increased incidence of many non-communicable diseases, including obesity, cardiovascular disease, metabolic syndrome, and type 2 diabetes (T2D). Dietary sugars are mainly hexoses, including glucose, fructose, sucrose and High Fructose Corn Syrup (HFCS). These sugars are primarily absorbed in the gut as fructose and glucose. The consumption of high sugar beverages and processed foods has increased significantly over the past 30 years. Here, we summarize the effects of consuming high levels of dietary hexose on rheumatoid arthritis (RA), multiple sclerosis (MS), psoriasis, inflammatory bowel disease (IBD) and low-grade chronic inflammation. Based on these reported findings, we emphasize that dietary sugars and mixed processed foods may be a key factor leading to the occurrence and aggravation of inflammation. We concluded that by revealing the roles that excessive intake of hexose has on the regulation of human inflammatory diseases are fundamental questions that need to be solved urgently. Moreover, close attention should also be paid to the combination of high glucose-mediated immune imbalance and tumor development, and strive to make substantial contributions to reverse tumor immune escape.

Mannose: A Sweet Option in the Treatment of Cancer and Inflammation.

As a natural sugar, mannose is a type of hexose that is abundant in many different types of fruits. Since mannose is rarely used for glycolysis in mammals, studies on the role of mannose have not attracted much attention. Glycosylation of specific proteins was thought to be the major function of mannose. Surprisingly, during the past few years, mannose was found to be effective in promoting immune tolerance and suppressing inflammatory diseases related to autoimmunity and allergy. Moreover importantly, mannose was also found to be efficient in suppressing tumors by suppressing glycolysis and enhancing chemotherapeutic agents. In this review, we summarize the recent studies of mannose on antitumor properties and anti-inflammatory characteristics. We emphasize that mannose could play a beneficial role in the treatment of a variety of diseases, including cancers and inflammatory diseases, and could be a novel therapeutic strategy that deserves continued evaluation.

[Research Progress in High-Sugar Diet and Inflammatory Diseases].

High-sugar diet causes various diseases, including insulin resistance, diabetes, and non-alcoholic fatty liver disease (NAFLD). In recent years, as researchers probe deeper and deeper into issues concerning high-sugar diet, the impact of high-sugar diet on inflammatory diseases such as autoimmune diseases and infectious diseases has been gradually uncovered and clarified. In this review, we summarized the current research progress on high-sugar diet and inflammatory diseases, and suggested that a high-sugar diet based on high intake of glucose and fructose may be an important factor inducing the exacerbation of chronic inflammatory diseases such as autoimmune diseases. Moreover, we also summarized the regulatory mechanisms through which high-sugar diet induces exacerbation of inflammatory diseases. In addition, we stated that conducting extensive clinical research and research in real-life settings and pursuing thorough investigation to reveal the different involvement of high-glucose diet and high-fructose diet in immune regulation are the key scientific issues that need urgent solutions in the future.

In Vivo Generation of SSA/Ro Antigen-Specific Regulatory T Cells Improves Experimental Sjögren's Syndrome in Mice.

OBJECTIVE: Sjögren's syndrome (SS) is a systemic autoimmune disease, and T cells play an important role in the initiation and perpetuation of the disease. In this study, we developed an immunotherapy for NOD/LtJ mice with SS-like symptoms by combining a transient depletion of CD4+ T cells with the administration of autoantigen-specific peptide Ro480. METHODS: NOD/LtJ mice were treated with single anti-CD4 monoclonal antibody (mAb) followed 2 days later by a series of 6 intraperitoneal injections of Ro480-494 every other day. Salivary flow rates were determined pre- and posttreatment once a week. Mice were euthanized 6 weeks after the initial anti-CD4 mAb treatment, salivary glands (SGs) were collected for analyses of histologic disease scores and inflammatory cell infiltration, polymerase chain reaction determination of genes was conducted, and flow cytometry analysis including major histocompatibility complex class II tetramer staining of immune cells was performed. In addition, adoptive transfer of Treg cells was administrated to investigate the function of the newly generating Treg cells in vivo. RESULTS: The combination of anti-CD4 mAb with autoantigen-specific peptide Ro480 generated SSA/Ro antigen-specific Treg cells in vivo, which can suppress interferon-γ production of CD4+ T cells and inflammation infiltration in SGs and maintain the function of SGs. CONCLUSION: Our findings provide a new approach to generating antigen-specific Treg cells in vivo for SS treatment, which may have implications for potential therapy for patients with SS.

Role of Cytokines in Thymic Regulatory T Cell Generation: Overview and Updates.

CD4+CD25+Foxp3+ Regulatory (Treg) T cells are mainly generated within the thymus. However, the mechanism of thymic Treg cell (tTreg cell) generation remains to be fully revealed. Although the functions of TCR/CD28 co-stimulation have been widely accepted, the functions of cytokines in the generation of tTreg cells remain highly controversial. In this review, we summarize the existing studies on cytokine regulation of tTreg cell generation. By integrating the key findings of cytokines in tTreg cell generation, we have concluded that four members of γc family cytokines (IL-2, IL-4, IL-7 and IL-15), transforming growth factor ß (TGF-ß), and three members of TNF superfamily cytokines (GITRL, OX40L and TNF-α) play vitally important roles in regulating tTreg cell generation. We also point out all disputed points and highlight critical scientific questions that need to be addressed in the future.

High fructose diet: A risk factor for immune system dysregulation.

Excessive intake of sweets is a predisposing factor for metabolic disorders, and fructose, as one of the major dietary sugars in the diet, has been shown to be a major cause of obesity, diabetes, and metabolic syndrome. These disorders are usually associated with immune dysfunction. Therefore, exploring the effects of a high fructose diet on the immune system may provide insight into the underlying mechanisms of these diseases. We synthesized the available evidence to suggest that excessive fructose intake disrupts the body's immune homeostasis by promoting immune cell metabolic rearrangements, alterations in gut microbial community structure, and intestinal barrier permeability. Indeed, not only does fructose itself affect immune system homeostasis, but its metabolites also have a profound influence. The metabolites from fructolysis are mainly produced in the small intestine and liver and subsequently enter the systemic circulation. Elevated levels of fructose metabolites, such as uric acid, FFAs, and lactate, are closely associated with oxidative stress and local tissue and organ inflammatory responses. In this review, we will focus on the link between fructose and inflammatory responses. In the meanwhile, we will also briefly summarize the studies of cancer development and immune escape mediated by fructose, as it might be beneficial for cancer immunotherapy.

Treg deficiency-mediated TH 1 response causes human premature ovarian insufficiency through apoptosis and steroidogenesis dysfunction of granulosa cells.

Immune dysregulation has long been proposed as a component of premature ovarian insufficiency (POI), but the underlying mediators and mechanisms remain largely unknown. Here we showed that patients with POI had augmented T helper 1 (TH 1) responses and regulatory T (Treg ) cell deficiency in both the periphery and the ovary compared to the control women. The increased ratio of TH 1:Treg cells was strongly correlated with the severity of POI. In mouse models of POI, the increased infiltration of TH 1 cells in the ovary resulted in follicle atresia and ovarian insufficiency, which could be prevented and reversed by Treg cells. Importantly, interferon (IFN) -γ and tumor necrosis factor (TNF) -α cooperatively promoted the apoptosis of granulosa cells and suppressed their steroidogenesis by modulating CTGF and CYP19A1. We have thus revealed a previously unrecognized Treg cell deficiency-mediated TH 1 response in the pathogenesis of POI, which should have implications for therapeutic interventions in patients with POI.