Th17 Cells Research Articles

Virulence‐Free Reconstituted Synthetic Nanopathogen Empowered by Timely‐Activating TLR Agonist Promotes Heterologous Cancer Immunotherapy with Depletion of Tumor‐Specific Treg Cells

AbstractThe heterologous immunity of live pathogens leads to the emergence of this approach as a pivotal component in cancer immunotherapy. However, virulence, inflammatory‐related toxicity, and the induction of Treg cells after treatment hinder their clinical translation. Here, to exploit the heterologous immunity of live pathogens without risks, a virulence‐free reconstituted synthetic nanopathogen (RSnP) is developed by the cell wall skeleton of disrupted Mycobacterium bovis and the incorporation of timely‐activating Toll‐like receptor 7/8 agonists of which multifaceted activities can be promoted by endolysosomal enzymes. Immunization with RSnP, even without tumor‐specific antigens, exhibits potent antitumor efficacy against melanoma, breast cancer, and bladder cancer by promoting antitumor effector cells (CD8+ T cells, NK cells, M1 macrophages, and Th17 cells) and proinflammatory cytokines (IL‐12p70, TNF‐α, and IL‐6) while simultaneously mitigating immunosuppressive myeloid cells (MDSCs and M2 macrophages) in the tumor microenvironment, surpassing the therapeutic efficacies of approved live‐BCG drug and mRNA vaccine. The increase in CCR8+Foxp3+ Treg cells induced to counteract RSnP treatment can be attenuated by anti‐CCR8 antibody, a depletion antibody for tumor‐specific Treg cells, to synergize therapeutic efficacy with relieved autoimmunity. RSnP can be a therapeutic nanomedicine platform across heterologous cancers and emerging infectious virus variants with minimized toxicity.

Elevated, Interleukin-21 expression is correlated with systemic sclerosis’ severity in Tunisian patients

Systemic sclerosis (SSc), a rare and lethal autoimmune disorder where patients presents diverse clinical features, therefore unravelling a potential biomarker within a specific cohort is crucial for improving patient care, especially for rare diseases.This study sought to identify potential biomarkers in Tunisian SSc patients. Gene expression analysis of interleukins (IL)-21 and IL-22 in peripheral blood mononuclear cells, using quantitative real-time polymerase chain reaction (qrt-pcr), revealed upregulated IL-21 and downregulated IL-22 in SSc patients compared to healthy controls. Notably, IL-21 overexpression in patients correlated with pulmonary complications, a severe SSc manifestation. Interestingly, flow cytometry analysis displayed no difference in Th17 cells between groups, suggesting that Th17 might not be the primary drivers of cytokine dysregulation. The hypothesis was supported by qRT-PCR, which analysed two key genes: IL-17A and RORγt. Finally, we examined RNA sequencing data to further validate our hypothesis.Collectively, our study provides novel insights into the cytokine landscape of SSc in Tunisian patients, highlighting a dysregulation in IL-21 and IL-22 expression, and suggesting that IL-21 could be a potential biomarker of severity.

Immunologic Profiling of CSF in Subarachnoid Neurocysticercosis Reveals Specific Interleukin-10-Producing Cell Populations During Treatment.

Subarachnoid neurocysticercosis (SANCC) is the most severe form of Taenia solium CNS infection and accounts for the majority of neurocysticercosis-associated mortality. Inflammation is important in the treatment of SANCC because overactivity can lead to serious complications, but excessive suppression may be counterproductive toward parasite eradication. A relative abundance of CSF IL-10 to IL-12 has been associated with increased treatment duration for patients with SANCC, suggesting that IL-10 plays an important role in this disease process. To better understand SANCC immunology and the major sources of IL-10 during anthelmintic treatment, we took an unbiased and comprehensive approach to phenotype the immune cell populations in the CSF and peripheral blood of patients with SANCC. Eight samples of CSF cells collected from 5 patients with SANCC during treatment were evaluated using single-cell RNA sequencing. Matched CSF and peripheral blood mononuclear cells from 4 patients were assessed using flow cytometry. Staining for extracellular and intracellular markers allowed for the characterization of IL-10-producing T cells. The CSF during SANCC contains a diversity of immune cell populations including multiple myeloid and lymphoid populations. Although there were changes in the composition of CSF cells during treatment, the largest population at both early and late time points was CD4+ T cells. Within this population, we identified 3 sources of IL-10 unique to SANCC CSF compared with controls: natural regulatory T cells (nTregs), induced regulatory T cells (iTregs), and Th17 cells. The abundance and phenotype of these IL-10-producing populations differed between CSF and blood in patients with SANCC, but iTregs were the single most productive population in the CSF. During treatment, these IL-10 producers persisted in consistent proportions despite decreases in parasite antigen over time. This profile of immune cell populations in the CSF provides a comprehensive blueprint of the local and systemic immunology associated with SANCC. The identification of IL-10-producing cells in the CSF and peripheral blood deepens our understanding of the immunosuppressive phenotype that deters SANCC treatment success. Finally, the discovery that these IL-10 producers persist throughout treatment highlights the endurance of these populations in the CNS.

Targeting of the IL-5 pathway in severe asthma reduces mast cell progenitors

BackgroundTherapies targeting interleukin-5 (IL-5) or its receptor (IL-5Rα) are currently used to treat patients with severe eosinophilic asthma. ObjectiveTo investigate the impact of anti-IL-5 and anti-IL-5Rα biological therapies on mast cells (MCs) and their progenitors. MethodsSurface IL-5Rα expression was investigated on MCs and their progenitors in mouse lungs and bone marrow, and in human lungs and blood. Isolated human MC progenitors cultured in the presence or absence of IL-5 were analyzed in vitro. Circulating MC progenitors were quantified in patients with severe asthma, before and after anti-IL-5 (mepolizumab) or anti-IL-5Rα (benralizumab) therapy. Gene expression analysis of MC progenitors was performed before and after anti-IL-5Rα therapy. ResultsApproximately 50% of the human primary lung MCs, and 30% of the human MC progenitors from individuals with allergic asthma expressed IL-5Rα. In patients with mild-to-moderate allergic asthma and mice with acute allergic airway inflammation, the fraction of IL-5Rα + MC progenitors was elevated. Additionally, IL-5 promoted the proliferation and/or survival of isolated human MC progenitors. Further, patients with severe asthma from two independent cohorts demonstrated a reduction of blood MC progenitors after anti-IL-5 or anti-IL-5Rα treatment. This was associated with improved asthma control, as well as a decline in both blood eosinophils and Th2 cells. Finally, the blood MC progenitors remaining after anti-IL-5Rα (benralizumab) treatment exhibited a downregulated expression of genes involved in growth and proliferation. ConclusionThis study introduces the possibility that the clinical effects of targeting IL-5/IL-5Rα in severe asthma also may involve reduction of MC populations.

Single-cell and machine learning approaches uncover intrinsic immune-evasion genes in the prognosis of hepatocellular carcinoma

Background and aimsHepatocellular carcinoma (HCC) is a tumor of high heterogeneity and complexity, which poses significant challenges to effective treatment and patient prognosis because of its immune evasion characteristics. To address these issues, single-cell technology and machine learning methods have emerged as a promising approach to identify genes associated with immune escape in HCC. This study aimed to develop a prognostic risk score model for HCC by identifying intrinsic immune-evasion genes (IIEGs) through single-cell technology and machine learning, providing insights into immune infiltration, enhancing predictive accuracy, and facilitating the development of more effective treatment strategies. Materials and methodsThe study utilized data from The Cancer Genome Atlas database to analyze gene expression profiles and clinical data related to intrinsic immune evasion in patients with HCC. Various tools, including the Human Protein Atlas, cBioPortal, single-cell analysis, machine learning, and Kaplan-Meier plot, were used to analyze IIEGs. Functional enrichment analysis was conducted to explore potential mechanisms. In addition, the abundance of infiltrating cells in the tumor microenvironment was investigated using single-sample gene set enrichment analysis, CIBERSORT, xCELL, and tumor immunophenotype algorithms. The expression of glycosylphosphatidylinositol anchor attachment 1 (GPAA1) was examined in the clinical sample of HCC by quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemical staining. ResultsUnivariate Cox analysis identified 63 IIEGs associated with the prognosis of HCC. Using random forest, least absolute shrinkage and selection operator regression analysis, and support vector machine, a risk score model consisting of six IIEGs (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), phosphatidylinositol glycan anchor biosynthesis class U (PIGU), endoplasmic reticulum membrane protein complex subunit 3 (EMC3), centrosomal protein 55 (CEP55), autophagy-related 10 (ATG10), and GPAA1) developed, which was validated using 10 pairs of HCC and adjacent non-cancerous samples. Based on the calculated median risk score, HCC samples were categorized into high- and low-risk groups. The Kaplan-Meier curve analysis showed that the high-risk group had a worse prognosis compared with the low-risk group. Time-dependent receiver operating characteristic analysis demonstrated the accurate predictive capability of the risk score model for HCC prognosis. Furthermore, immune infiltration analysis showed a positive correlation between the risk score model and 40 immune checkpoint genes as well as Th2 cells. ConclusionsA prognostic risk score model was formulated by six IIEG signatures and showed promise in predicting the prognosis of patients diagnosed with HCC. The utilization of the IIEG risk score as a novel prognostic index, together with its significance as a valuable biomarker for immunotherapy in HCC, provides benefit for patients with HCC in determining therapeutic strategies for clinical application.

The role of S-nitrosoglutathione reductase (GSNOR) in T cell-mediated immunopathology of experimental autoimmune encephalomyelitis (EAE)

Previously, we reported that both S-nitrosoglutathione (GSNO), a carrier of cellular nitric oxide, and N6022, an injectable form of GSNO reductase (GSNOR) inhibitor that increases endogenous GSNO levels, alleviate experimental autoimmune encephalomyelitis (EAE) in mice by suppressing Th1 and Th17 immune responses. Building on these findings, we explored the role of GSNOR in EAE pathogenesis and evaluated the efficacy of an orally active GSNOR inhibitor (N91115) in treating the EAE disease. EAE mice exhibited heightened expression/activity of GSNOR in the spinal cord, and the knockout of the GSNOR gene resulted in much milder clinical manifestations of EAE, with lower degrees of demyelination and axonal loss, reduced microglial and astrocyte activations, as well as suppressed Th1 and Th17 cell responses, alongside bolstered Treg immune responses. Next, we evaluated the efficacy of N91115 against EAE immunopathology. Consistent with our findings in GSNOR deficient EAE mice, daily N91115 administration reduced clinical EAE severity, with less spinal cord demyelination and axonal loss compared to untreated EAE mice. Furthermore, N91115 treated EAE mice showed diminished Th1 and Th17 immune responses and enhanced Treg responses. This observation underscores the potential of increased GSNOR expression and activity as a risk factor exacerbating EAE immunopathology, while simultaneously highlighting its potential as a target for modifying the disease. Furthermore, the balanced immune regulation provided by orally active N91115 (IL-6/IL-17a vs. IL-10) presents a promising alternative to immunosuppressive drugs, reducing the risk of opportunistic infections.

RETRACTION: Bach2 overexpression represses Th9 cell differentiation by suppressing IRF4 expression in systemic lupus erythematosus.

Y. Sheng, J. Zhang, K. Li, H. Wang, W. Wang, L. Wen, J. Gao, X. Tang, H. Tang, H. Huang, M. Cai, T. Yuan, L. Liu, X. Zheng, Z. Zhu and Y. Cui, "Bach2 Overexpression Represses Th9 Cell Differentiation by Suppressing IRF4 Expression in Systemic Lupus Erythematosus," FEBS Open Bio 11, no. 2 (2021): 395-403, https://doi.org/10.1002/2211-5463.13050. The above article, published online on 28 November 2020 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal Editor-in-Chief, Miguel A. De la Rosa; FEBS Press; and John Wiley and Sons Ltd. The retraction has been agreed following diagnostic errors identified by the authors in the patient samples used in this study. Based on the issues identified, the editors and authors consider the conclusions substantially compromised.

Decoding the role of HIF-1α in immunoregulation in Litopenaeus vannamei under hypoxic stress

Hypoxia poses a significant challenge to aquatic organisms, especially Litopenaeus vannamei (L. vannamei), which play a vital role in the global aquaculture industry. Hypoxia-inducible factor 1α (HIF-1α) is a pivotal regulator of the organism's adaptation to hypoxic conditions. To understand of how HIF-1α affects the immunity of L. vannamei under hypoxic conditions, we conducted a thorough study involving various approaches. These included observing tissue morphology, analyzing the expression of immune-related genes, assessing the activities of immune-related enzymes, and exploring immune-related pathways. Our study revealed that RNA interference (RNAi)-mediated knockdown of HIF-1α markedly reduced HIF-1α expression in the gill (75 to 95%), whereas the reduction ranged from 2 to 43% in the hepatopancreas. Knockdown of HIF-1α resulted in increased damage to both gill and hepatopancreatic tissues in hypoxic conditions. Additionally, immune-related genes, including Astakine (AST), Hemocyanin (HC), and Ferritin (FT), as well as immune-related enzymes such as Acid Phosphatase (ACP), Alkaline Phosphatase (AKP), and Phenoloxidase (PO), exhibited intricate regulatory patterns in response to hypoxia stress following the knockdown of HIF-1α. Transcriptome analysis revealed that HIF-1α knockdown significantly impacts multiple signaling pathways, including the JAK-STAT signaling pathway, Th17 cell differentiation pathways, PI3K-Akt signaling pathway, ErbB signaling pathway, MAPK signaling pathway, chemokine signaling pathway, ribosomal pathways, apoptosis, lysosomes and arachidonic acid metabolism. These alterations disrupt the organism's immune balance and interfere with normal metabolic processes, potentially leading to various immune-related diseases. We speculate that the weakened immune response resulting from HIF-1 inhibition is due to the reduced metabolic capacity, and the existence of a direct regulatory relationship between them requires further exploration. This study greatly advances our understanding of the vital role that HIF-1α plays in regulating immune responses in shrimp under hypoxic conditions, thereby deepening our comprehension of this critical biological mechanism.

Activation of α2B/2C adrenergic receptor ameliorates ocular surface inflammation through enhancing regulatory T cell function

There is an unmet need for effectively treating dry eye disease (DED), a T cell-mediated chronic, inflammatory ocular surface disorder. Given the potential of nonneuronal adrenergic system in modulating T cell response, we herein investigated the therapeutic efficacy and the underlying mechanisms of a specific alpha 2 adrenergic receptor agonist (AGN-762, selective for α2B/2C receptor subtypes) in a mouse model of DED. Experimental DED was treated with the AGN-762 by oral gavage, either at disease induction or after disease establishment, and showed sustained amelioration, along with reduced expression of DED-pathogenic cytokines in ocular surface tissues, decreased corneal MHC-II+CD11b+ cells and lymphoid Th17 cells, and higher function of regulatory T cells (Treg). In vitro culture of DED-derived effector T helper cells (Teff) with AGN-762 failed to suppress Th17 response, while culture of DED-Treg with AGN-762 led to enhanced suppressive function of Treg and their IL-10 production. Adoptive transfer of AGN-762-pretreated DED-Treg in syngeneic B6.Rag1-/- mice effectively suppressed DED Teff-mediated disease and Th17 response, and the effect was abolished by the neutralization of IL-10. In conclusion, our findings demonstrate that α2B/2C adrenergic receptor agonism effectively ameliorates persistent corneal epitheliopathy in DED by enhancing IL-10 production from Treg and thus restoring their immunoregulatory function.

Enhanced cancer cell proliferation and aggressive phenotype counterbalance in breast cancer with high BRCA1 gene expression.

While comprehensive research exists on the mutation of the DNA repair gene BRCA1, limited information is available regarding the clinical significance of BRCA1 gene expression. Given that cancer cell proliferation is aggrevated by DNA repair, we hypothesized that high BRCA1 gene expression breast cancer (BC) might be linked with aggressive tumor biology and poor clinical outcomes. The cohorts: The Cancer Genome Atlas (TCGA, n = 1069), METABRIC (n = 1903), and SCAN-B (n = 3273) were utilzed to obtain data of 6245 BC patients. BC patients without BRCA1 mutation exhibited higher BRCA1 expression, which was associated with DNA repair functionality. However, no such correlation was observed with BRCA2 expression. The association of high BRCA1 expression with cancer cell proliferation was evidenced by significant enrichment of cell proliferation-related gene sets, higher histological grade, and proliferation score. Furthermore, increased levels of homologous recombination deficiency, intratumoral heterogeneity, and altered fractions were associated with high BRCA1 expression. Moreover, BC with high BRCA1 expression exhibited reduced infiltration of dendritic cells and CD8 T-cells, while showing increased infiltration of Th1 cells. Surprisingly, BRCA1 expression was not associated with the survival of BC irrespective of the subtypes. Conversely, BC with low BRCA1 expression enriched cancer aggravating pathway gene sets, such as Cancer Stem Cell-related signaling (NOTCH and HEDGEHOG), Angiogenesis, Epithelial-Mesenchymal Transition, Inflammatory Response, and TGF-beta signaling. Despite being linked to heightened proliferation of cancer cells and unassertive phenotype, BRCA1 expression did not show any association with survival in BC.

GPR55 antagonist CID16020046 suppresses DNCB-induced atopic dermatitis-like symptoms by suppressing Th1/Th2/Th17 populations in mice

G protein-coupled receptor 55 (GPR55) is a lipid-sensing receptor that plays a role as an immune mediator and is primarily upregulated during immune cell activation. There is a lack of knowledge about the role of GPR55 in allergic inflammatory diseases such as atopic dermatitis. The purpose of this study was to investigate the role of GPR55 through the use of its antagonist, CID16020046, in an atopic dermatitis mouse model. It was found that BALB/c mice develop lesions similar to those associated with atopic dermatitis following sensitization and repeated exposure to 1-chloro-2,4-dinitrobenzene (DNCB). It was found that CID16020046 (1 mg/kg, i. p.) alleviated the atopic dermatitis-like symptoms as well as immune dysregulation caused by DNCB. Based on histopathological analysis, CID16020046 reduced ear thickening and mast cell counts in the dermis. CID16020046 decreased DNCB-induced increases in serum IgE levels, as measured using enzyme-linked immunosorbent assays. A significant reduction in lymph node hypertrophy was also observed with CID16020046 as well as significant reductions in CD4+ T helper 1 (Th1), Th2, and Th17 cells in the lymph nodes. As a result of the administration of CID16020046, cytokines of Th1 (IFN-γ), Th2 (IL-4 and IL-13), and Th17 (IL-17 A) types were also reduced in the skin and lymph nodes. In conclusion, blocking GPR55 alleviates DNCB-induced atopic dermatitis-like symptoms, suggesting that GPR55 is a potential therapeutic target for allergic inflammatory diseases via immunoregulation.

Polysaccharides from Gaultheria leucocarpa var. yunnanensis (DBZP) alleviates rheumatoid arthritis through ameliorating gut microbiota

Gaultheria leucocarpa var. yunnanensis (Dianbaizhu) is a traditional Chinese herb for rheumatoid arthritis (RA). However, its macromolecular components have always been overlooked. This study aimed to investigate the chemical composition and effect on improving RA of polysaccharides from Dianbaizhu (DBZP). The results showed the yield of DBZP was 4.07 % ± 0.03 %, and it was composed of Mannose (6.63 %), ribose (1.33 %), rhamnose (4.53 %), glucuronic acid (2.95 %), galacturonic acid (32.29 %), glucose (13.78 %), galactose (22.97 %), xylose (3.94 %) and arabinose (11.59 %), with a large molecular weight distribution range. DBZP treatment could reduce the paws thickness and arthritis scores of collagen-induced arthritis (CIA) mice, and improve inflammatory cell infiltration, synovial hyperplasia, bone erosion, and deterioration. The abundance of several specific bacteria, such as Lactobacillus, Bacteroides, Alistipes, Mucispirillum, and Candidatus_Saccharimonas, and some metabolites in feces or urine, such as 11beta-hydroxytestosterone, pregnanediol 3-O-glucuronide, p-cresol sulfate and several amino acids and peptides, was also altered. The process of DBZP alleviating RA through gut microbiota involves affecting the digestion and metabolism of carbohydrates and protein, altering sex hormones levels, and regulating intestinal immune function, such as the differentiation and signaling of Th17 cells. These findings suggest that DBZP possesses a protective effect on CIA in mice via modulating gut microbiota.

Cell aggregation mediated by ACE2 deletion in Candida auris modulates fungal colonization and host immune responses in the skin.

Candida auris is an emerging multi-drug-resistant fungal pathogen that colonizes the skin and causes invasive infections in hospitalized patients. Multi-cellular aggregative phenotype is widely reported in the C. auris isolates, but its role in skin colonization and host immune response is not yet known. In this study, we generated aggregative phenotype by deleting the ACE2 gene in C. auris and determined the fungal colonization and host immune response using an intradermal mouse model of C. auris skin infection. Our results indicate that mice infected with ace2Δ strain had significantly lower fungal load after 3 and 14 days post-infections compared to the non-aggregative wild-type and the ACE2 reintegrated strain. The colonization of ace2Δ is associated with increased recruitment of CD11b+ Ly6G+ neutrophils and decreased accumulation of CD11b+ Ly6 Chi inflammatory monocytes and CD11b+ MHCII+ CD64+ macrophages. Furthermore, Th17 cells and type 3 innate lymphoid cells (ILCs) were significantly increased in the skin tissue of ace2Δ infected mice. Our findings suggest that aggregative phenotype mediated by ACE2 deletion in C. auris induces potent neutrophil and IL-17-mediated immune response and reduces fungal colonization in the skin.IMPORTANCEC. auris is a rapidly emerging fungal pathogen that can colonize hospitalized patients, especially in skin tissue, and cause invasive infections. C. auris isolates exhibit morphological heterogeneity, and the multicellular aggregative phenotype of C. auris is reported frequently in clinical settings. Understanding the role of fungal morphotypes in colonization, persistence, and immune response in the skin microenvironment will have potential applications in clinical diagnosis and novel preventive and therapeutic measures. Here, we utilized the murine model of intradermal infection and determined that the aggregative phenotype of C. auris as the result of ACE2 gene deletion elicits potential innate and adaptive immune responses in mice. These observations will help explain the differences in the skin colonization and immune responses of the aggregative morphotype of C. auris and open the door to developing novel antifungal therapeutics.

Oxymatrine attenuates chronic allograft rejection by modulating immune responses and inhibiting fibrosis

BackgroundChronic rejection (CR) is a significant obstacle to long-term allograft survival. Oxymatrine (OMT) is a prominent bioactive compound widely utilized in traditional Chinese medicine for the management of inflammatory disorders and it has considerable potential as a therapeutic candidate for the treatment of CR. MethodsWell-established major histocompatibility complex (MHC) class II mismatched B6 mice. C-H-2bm12-to-C57BL/6 mouse transplantation was used as a CR model. Hematoxylin and eosin (H&E) staining, immunohistochemistry, and Masson's trichrome staining were used to assess pathological changes in the grafts, and the percentages of immune cells were determined by flow cytometry. The effects of OMT on the regulation of CD4+ T cell differentiation and cytokine secretion were verified in vitro. ResultsOMT effectively alleviated pathological graft damage, characterized by chronic changes in intimal lesions, vasculopathy, and fibrosis and significantly prolonged cardiac allograft survival. OMT exerted its immunomodulatory effects by inhibiting T helper 1 (Th1) and T helper 17 (Th17) cell differentiation while promoting Treg differentiation both in vivo and in vitro. Further studies revealed that OMT inhibited the phosphorylation of mammalian target of rapamycin (mTOR), which is a potential mechanism underlying its immunosuppressive effects. OMT also inhibited the activation of B cells and the production of donor-specific antibody (DSA). In addition, OMT effectively alleviated chronic changes in fibrosis in cardiac allografts, and these changes may be related to the inhibition of the transforming growth factor-β (TGF-β)-Smad 2/3 pathway. ConclusionsOMT attenuated CR by modulating the immune response and inhibiting graft fibrosis. Further in-depth investigations of OMT may provide valuable insights into the development of novel therapeutic strategies for CR inhibition.

Dual-Action Psoriasis Therapy: Antiproliferative and Immunomodulatory Effects via Self-Locking Microneedles.

Psoriasis is a chronic, immune-mediated disorder characterized by immune regulation disorders and abnormal keratinocyte proliferation. Deucravacitinib (Deu), a selective oral Tyrosine Kinase 2 (TYK2) inhibitor, shows promise in treating psoriasis but may cause systemic side effects and fail to address persistent localized thickened lesions. Herein, a self-locking microneedle (MN) patch with a polyvinyl alcohol (PVA) inner ring loaded with Deu is developed, designed to penetrate the transdermal barriers and dissolve rapidly, downregulating the IL-23/IL-17 pathway and serve as the first line of defense against the spread of skin-originated inflammation. Additionally, Calcipotriol (Cal), a vitamin D derivative, is incorporated into a methacrylated hyaluronic acid (HAMA) backing layer and outer ring that mimics occlusive administration, maintaining localized skin surface retention for prolonged anti-proliferative therapy. The Deu@Cal MN demonstrates satisfactory adhesiveness due to swelling-mediated mechanical interlocking via the outer ring, ensuring targeted drug release at lesion site. Besides its effectiveness in alleviating both skin inflammation and proliferation, it inhibits the differentiation of Th17 cells in the spleen, suggesting potential to reduce systemic inflammation. These findings offer a new therapeutic approach for treating psoriasis and other autoimmune and inflammatory conditions.

Th17/Treg cell balance in patients with papillary thyroid carcinoma: a new potential biomarker and therapeutic target

Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid carcinoma. The most effective treatment for PTC is surgical resection, and patients who undergo surgery have good survival outcomes, but some patients have distant metastasis or even multiorgan metastases at the time of initial diagnosis. Distant metastasis is associated with poorer prognosis and a higher mortality rate. Helper T lymphocyte 17 (Th17) cells and regulatory T lymphocytes (Tregs) play different roles in PTC, and the Th17/Treg balance is closely related to the progression of PTC. Th17 cells play anticancer roles, whereas Tregs play cancer-promoting roles. A Th17/Treg imbalance promotes tumor progression and accelerates invasive behaviors such as tumor metastasis. Th17/Treg homeostasis can be regulated by the TGF‐β/IL‐2 and IL‐6 cytokine axes. Immune checkpoint inhibitors contribute to Treg/Th17 cell homeostasis. For PTC, monoclonal antibodies against CTLA-4, PD-1 and PD-L1 inhibit the activation of Tregs, reversing the Th17/Treg cell imbalance and providing a new option for the prevention and treatment of PTC. This article reviews the role of Tregs and Th17 cells in PTC and their potential targets, aiming to provide better treatment options for PTC.

Gelsolin regulates intestinal stem cell regeneration and Th17 cellular function

Intestinal stem cells (ISCs) are responsible for intestinal homeostasis and are important for the regeneration of damaged intestine. We established an ionizing radiation (IR)-induced intestinal injury model and observed that Gelsolin KO mice had increased radiosensitivity. The deletion of Gelsolin aggravated intestinal damage and reduced the number of ISCs after lethal IR. The intestinal organoid experiments showed that Gelsolin deletion inhibited ISCs function after IR. Notably, RNA sequencing and RT-PCR results showed IL-17 signaling pathway was down-regulated and Th17 cells differentiation was inhibited in Gelsolin KO mice. Moreover, recombinant IL-17 A ameliorated IR-induced intestinal injury and promoted ISCs regeneration. To figure out the role of Gelsolin in Th17 cells differentiation, flow cytometry was used and we found that Gelsolin targets Th17 cells functionality via the p-STAT3/RORγt axis. By establishing the co-culture system, we proved that Th17 cells promoted self-renewal and budding abilities in Gelsolin-deficient organoids. Finally, we found that Gelsolin was protective against DSS-induced colitis and that this protective effect was not specific or limited to the IR induced intestinal injury model. Based on these results, we proved Gelsolin maintained the regeneration of ISCs by sustaining Th17 cells functions via the p-STAT3/RORγt axis.Graphical abstract

Global research trends and prospects on immune-related therapy in ischemic stroke: a bibliometric analysis

BackgroundFollowing ischemic stroke, non-neuronal cells within the nervous system play a crucial role in maintaining neurovascular unit functions, regulating metabolic and inflammatory processes of the nervous system. Investigating the functions and regulation of these cells, particularly immune cells, deepens our understanding of the complex mechanisms of neuroinflammation and immune modulation after ischemic stroke and provides new perspectives and methods for immune-related therapy.MethodsThe annual distribution, journals, authors, countries, institutions, and keywords of articles published between 2015 and 2024 were visualized and analyzed using CiteSpace and other bibliometric tools.ResultsA total of 1,089 relevant articles or reviews were included, demonstrating an overall upward trend; The terms “cerebral ischemia,” “immune response,” “brain ischemia,” “cerebral inflammation,” “neurovascular unit,” and “immune infiltration,” etc. are hot keywords in this field.ConclusionIn recent years, research on immune-related therapy for ischemic stroke has focused on mechanisms of occurrence, protection and repair of the blood-brain barrier (BBB) by non-neuronal cells, and regulation of immunosuppression and inflammation. Among these, reducing BBB disruption to minimize secondary brain damage has become a hotspot. At the same time, the complex roles of immune responses have attracted attention, particularly the balance between regulatory T cells and Th17 cells in regulating neuroinflammation and promoting neurological function recovery, which is crucial to reduce secondary neuronal damage and improve prognosis, potentially establishing a pivotal frontier in this domain of investigation.

Immunomodulatory effect of mesenchymal stem cells-derived extracellular vesicles to modulate the regulatory T cells and Th1/Th2 imbalance in peripheral blood mononuclear cells of patients with allergic rhinitis.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown promising immunomodulatory capabilities for a variety of clinical conditions. However, the potential regulatory mechanisms of MSC-EVs in allergic rhinitis (AR) remain unexplored. The present study was designed to investigate the immunomodulatory effect of MSC-EVs in patients with AR. Peripheral blood mononuclear cells (PBMCs) were isolated from AR patients. The number of peripheral CD4+Foxp3+IL-17+, CD4+Foxp3+IL-17- and CD4+Foxp3-IL-17+ T cells in healthy controls and AR patients were evaluated using flow cytometry. Therapeutic effect of MSC-EVs was determined by detecting IFN-γ, IL-4, IL-17 and IL-10 cytokines in supernatant by ELISA and flow cytometry. The mean fluorescence intensity (MFI) was calculated in PBMCs for IL-10, IL-17 and TGF-β on T cells after MSC-EVs treatment. Bioinformatic analysis of microRNA was performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. CD4+Foxp3+IL-17+ T cells expression in PBMCs was higher in the AR group and the balance of Treg/Th17 was tilted towards Th17 cells. Supernatant from AR patients revealed that MSC-EVs treatment upregulated IL-10 and IFN-γ, and downregulated IL-4 and IL-17. EVs treatment effectively re-established Th1(CD4+IFN-γ+cells)/Th2(CD4+IL-4+cells) balance, reduced CD4+IL-17+ and increased CD4+IL-10+ and CD4+TGF-β+ cells. The MFI of IL-10 and TGF-β in CD4+CD25+CD127- T cells were higher, whereas lower levels of IL-17 were observed. Bioinformatic analysis revealed that the TGF-β, Wnt signalling pathways and STAT5 transcription factor might mechanistically support the immunomodulatory effect of MSC-EVs. This study presents the immunomodulatory effect of MSC-EVs in PBMCs from AR patients. The results provide a new therapeutic strategy for AR.

Fecal microbiota transplantation against moderate-to-severe atopic dermatitis: A randomized, double-blind controlled explorer trial.

Fecal microbiota transplantation (FMT) is a novel treatment for inflammatory diseases. Herein, we assess its safety, efficacy, and immunological impact in patients with moderate-to-severe atopic dermatitis (AD). In this randomized, double-blind, placebo-controlled clinical trial, we performed the efficacy and safety assessment of FMT for moderate-to-severe adult patients with AD. All patients received FMT or placebo once a week for 3 weeks, in addition to their standard background treatments. Patients underwent disease severity assessments at weeks 0, 1, 2, 4, 8, 12, and 16, and blood and fecal samples were collected for immunologic analysis and metagenomic shotgun sequencing, respectively. Safety was monitored throughout the trial. Improvements in eczema area and severity index (EASI) scores and percentage of patients achieving EASI 50 (50% reduction in EASI score) were greater in patients treated with FMT than in placebo-treated patients. No serious adverse reactions occurred during the trial. FMT treatment decreased the Th2 and Th17 cell proportions among the peripheral blood mononuclear cells, and the levels of TNF-α, and total IgE in serum. By contrast, the expression levels of IL-12p70 and perforin on NK cells were increased. Moreover, FMT altered the abundance of species and functional pathways of the gut microbiota in the patients, especially the abundance of Megamonas funiformis and the pathway for 1,4-dihydroxy-6-naphthoate biosynthesis II. FMT was a safe and effective therapy in moderate-to-severe adult patients with AD; the treatment changed the gut microbiota compositions and functions.