Research progress of the application of mesenchymal stem cells in chronic inflammatory systemic diseases

Chronic inflammatory systemic diseases are the result of the body's immune imbalance, with a long course and recurring episodes. Immunosuppressants are the main treatment, but not all patients respond well to it. Being capable of both self-renewal and differentiation into multiple tissue cells and low immunogenicity, mesenchymal stem cell is a promising treatment for chronic inflammatory systemic diseases. In this article, we describe the research progress and clinical application of mesenchymal stem cells in chronic inflammatory systemic diseases and look for influencing factors and biomarkers that can predict the outcome of patient with mesenchymal stem cell transplantation.

Deacetylasperulosidic Acid Ameliorates Pruritus, Immune Imbalance, and Skin Barrier Dysfunction in 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis NC/Nga Mice

The prevalence of atopic dermatitis (AD), a disease characterized by severe pruritus, immune imbalance, and skin barrier dysfunction, is rapidly increasing worldwide. Deacetylasperulosidic acid (DAA) has anti-atopic activity in the three main cell types associated with AD: keratinocytes, mast cells, and eosinophils. Our study investigated the anti-atopic activity of DAA in 2,4-dinitrochlorobenzene-induced NC/Nga mice. DAA alleviated the symptoms of AD, including infiltration of inflammatory cells (mast cells and eosinophils), epidermal thickness, ear thickness, and scratching behavior. Furthermore, DAA reduced serum IgE, histamine, and IgG1/IgG2a ratio and modulated the levels of AD-related cytokines and chemokines, namely interleukin (IL)-1β, IL-4, IL-6, IL-9, IL-10, IL-12, tumor necrosis factor-α, interferon-γ, thymic stromal lymphopoietin, thymus and activation-regulated chemokine, macrophage-derived chemokine, and regulated on activation the normal T cell expressed and secreted in the serum. DAA restored immune balance by regulating gene expression and secretion of Th1-, Th2-, Th9-, Th17-, and Th22-mediated inflammatory factors in the dorsal skin and splenocytes and restored skin barrier function by increasing the expression of the pro-filaggrin gene and barrier-related proteins filaggrin, involucrin, and loricrin. These results suggest DAA as a potential therapeutic agent that can alleviate the symptoms of AD by reducing pruritus, modulating immune imbalance, and restoring skin barrier function.

Gut Microbiota as Regulators of Th17/Treg Balance in Patients With Myasthenia Gravis

Myasthenia gravis (MG) is an acquired neurological autoimmune disorder characterized by dysfunctional transmission at the neuromuscular junction, with its etiology associated with genetic and environmental factors. Anti-inflammatory regulatory T cells (Tregs) and pro-inflammatory T helper 17 (Th17) cells functionally antagonize each other, and the immune imbalance between them contributes to the pathogenesis of MG. Among the numerous factors influencing the balance of Th17/Treg cells, the gut microbiota have received attention from scholars. Gut microbial dysbiosis and altered microbial metabolites have been seen in patients with MG. Therefore, correcting Th17/Treg imbalances may be a novel therapeutic approach to MG by modifying the gut microbiota. In this review, we initially review the association between Treg/Th17 and the occurrence of MG and subsequently focus on recent findings on alterations of gut microbiota and microbial metabolites in patients with MG. We also explore the effects of gut microbiota on Th17/Treg balance in patients with MG, which may provide a new direction for the prevention and treatment of this disease.

Mechanism of miR-181a-5p in Regulatory T/T-Helper 17 Immune Imbalance and Asthma Development in Mice with Allergic Rhinitis

<b><i>Introduction:</i></b> Allergic rhinitis (AR) is an immune disorder and also a risk factor of asthma. microRNAs (miRNAs) are implicated in autoimmune diseases, including RA. This study investigated effect of miR-181a-5p on regulatory T (Treg)/ T-helper (Th) 17 immune imbalance in AR. <b><i>Methods:</i></b> A murine model of AR was established and treated with lentivirus modified miR-181a-5p. The allergic symptoms of mice were examined. The contents of Th17-related cytokines (interferon [IFN]-γ and interleukin [IL]-6), Treg-related cytokine (IL-10), and Treg-specific nuclear transcription factor (Foxp3) in nasal mucosa and lung tissues were determined. The proportion of Treg and Th17 cells was analyzed by flow cytometry. The level of ovalbumin-specific immunoglobulin E in the serum, and the contents of IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid and IFN-γ, IL-6, and IL-10 in nasal lavage fluid were measured. The targeting relationship between miR-181a-5p and high mobility group box chromosomal protein 1 (HMGB1) was verified. HMGB1 and receptor for advanced glycation end products (RAGE) expression in RA were determined, and the interaction between HMGB1 and RAGE was detected. <b><i>Results:</i></b> miR-181a-5p expression was reduced in AR mice. miR-181a-5p overexpression attenuated allergic behaviors, alleviated Treg/Th17 imbalance, and delayed asthma development. HMGB1 and RAGE were elevated in AR mice. miR-181a-5p targeted HMGB1, and HMGB1 bound to RAGE, while miR-181a-5p overexpression reduced the binding between them. Activating HMGB1/RAGE reversed the protective effect of miR-181a-5p overexpression on AR and induced the development of asthma. <b><i>Conclusion:</i></b> miR-181a-5p overexpression reduced the binding of HMGB1 and RAGE by inhibiting HMGB1, thus alleviating Treg/Th17 immune imbalance and blocking AR from developing into asthma.

An altered skin microbiome is the most important symptom of atopic dermatitis.

Fast traslate Icon translate Fast traslate Icon translate The progressive increase in the incidence of atopic dermatitis among children, an increase in persistence in adulthood, combined with an inevitable decrease in the quality of life of patients, determine the relevance of studying the mechanisms of the development of this disease not only for dermatology, but also for the entire health care system. Thus, the prerequisites for the emergence of new concepts of pathogenesis and the search for the most effective therapeutic modalities arise. At the moment, atopic dermatitis is considered as the interaction of endogenous (impaired immune response, insufficient function of the epidermal barrier) and exogenous (exposure to allergens, chemical or physical irritants, microorganisms) factors. Environmental factors such as temperature and humidity, genetic makeup, antibiotic use, and good hygiene play a critical role in the maintenance and stability of the skin microbiome. Normally, the skin microbiota is mainly formed by bacteria of the genus Staphylococcus, Propionibacterium, Corynebacterium and Streptococcus. While in patients with AD, in 70% of cases, there is colonization of Staphylococcus aureus on the affected skin, in 39% on intact skin, which secondarily contributes to the development of immune imbalance and increased skin xerosis. This fact determines the importance of the use of basic therapy, which, on the one hand, helps to strengthen the epidermal barrier, and on the other hand, normalizes the microbiome of the skin, reducing the colonization of Staphylococcus aureus.

Fecal Microbiota Transplantation Controls Progression of Experimental Autoimmune Hepatitis in Mice by Modulating the TFR/TFH Immune Imbalance and Intestinal Microbiota Composition

Intestinal microbiota (IM) dysbiosis contributes to the development of autoimmune hepatitis (AIH). This study aimed to investigate the potential effect of fecal microbiota transplantation (FMT) in a murine model of experimental AIH (EAH), a condition more similar to that of AIH patients. Changes in the enteric microbiome were determined in AIH patients and EAH mice. Moreover, we established an experimental model of secondary EAH mice harboring dysbiosis (ABx) to analyze the effects of therapeutic FMT administration on follicular regulatory T (TFR) and helper T (TFH) cell imbalances and IM composition in vivo. Alterations of the IM composition and bacterial translocation occurred in AIH patients compared to nonalcoholic fatty liver disease patients and healthy controls (HCs). Therapeutic FMT significantly attenuated liver injury and bacterial translocation and improved the imbalance between splenic TFR cells and TFH cells in ABx EAH mice. Furthermore, therapeutic FMT also partially reversed the increasing trend in serum liver enzymes (ALT and AST) of CXCR5−/−EAH mice on the 28th day. Finally, therapeutic FMT could effectively restore antibiotic-induced IM dysbiosis in EAH mice. Taken together, our findings demonstrated that FMT was capable of controlling hepatitis progression in EAH mice, and the associated mechanism might be involved in the regulation of the TFR/TFH immune imbalance and the restoration of IM composition.

HUWE1 Causes an Immune Imbalance in Immune Thrombocytopenic Purpura by Reducing the Number and Function of Treg Cells Through the Ubiquitination Degradation of Ets-1

Background: Immune thrombocytopenic purpura (ITP) is an autoimmune bleeding disorder and the decreased number and immunosuppressive dysfunction of Treg cells are key promoters of ITP. However, their mechanisms in ITP development have not been fully clarified.Methods: HUWE1 mRNA and protein levels in CD4+ T cells in peripheral blood from ITP patients were assessed by quantitative real-time PCR and Western blot. HUWE1 function in ITP was estimated using flow cytometry, enzyme-linked immunosorbent assay and immunosuppression assay. Besides, the HUWE1 mechanism in reducing the number and function of Treg cells in ITP was investigated by immunoprecipitation, cycloheximide-chase assay, ubiquitin experiment and immunofluorescence assay.Results: HUWE1 expression was elevated in CD4+ T cells in peripheral blood from ITP patients and HUWE1 mRNA level was negatively correlated with platelet counts and Treg cell percentage. Moreover, the interference with HUWE1 increased the number of Treg cells and enhanced its immunosuppressive function, and the HUWE1 overexpression produced the opposite results. For the exploration of mechanism, HUWE1 interacted with E26 transformation-specific-1 (Ets-1) and this binding was dependent on the negative regulation of the phosphorylation level of Ets-1 (Thr38) and HUWE1 facilitated the ubiquitin degradation of Ets-1 protein to restrain Treg cell differentiation and weaken their immunosuppressive functions. The in vivo assay confirmed that the HUWE1 inhibitor alleviated ITP in mice.Conclusion: HUWE1 induced the immune imbalance in ITP by decreasing the number and weakening the function of Treg cells through the ubiquitination degradation of Ets-1.