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At least 19 recordsLinked to original sources
PubMed2006

Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides.

Th17 cells are a distinct lineage of effector CD4(+) T cells characterized by their production of interleukin (IL)-17. We demonstrate that Th17 cells also expressed IL-22, an IL-10 family member, at substantially higher amounts than T helper (Th)1 or Th2 cells. Similar to IL-17A, IL-22 expression was initiated by transforming growth factor beta signaling in the context of IL-6 and other proinflammatory cytokines. The subsequent expansion of IL-22-producing cells was dependent on IL-23. We further demonstrate that IL-22 was coexpressed in vitro and in vivo with both IL-17A and IL-17F. To study a functional relationship among these cytokines, we examined the expression of antimicrobial peptides by primary keratinocytes treated with combinations of IL-22, IL-17A, and IL-17F. IL-22 in conjunction with IL-17A or IL-17F synergistically induced the expression of beta-defensin 2 and S100A9 and additively enhanced the expression of S100A7 and S100A8. Collectively, we have identified IL-22 as a new cytokine expressed by Th17 cells that synergizes with IL-17A or IL-17F to regulate genes associated with skin innate immunity.

Animals↗
PubMed2024

Class IIa HDAC4 and HDAC7 cooperatively regulate gene transcription in Th17 cell differentiation.

Class II histone deacetylases (HDACs) are important in regulation of gene transcription during T cell development. However, our understanding of their cell-specific functions is limited. In this study, we reveal that class IIa Hdac4 and Hdac7 (Hdac4/7) are selectively induced in transcription, guiding the lineage-specific differentiation of mouse T-helper 17 (Th17) cells from naive CD4+ T cells. Importantly, Hdac4/7 are functionally dispensable in other Th subtypes. Mechanistically, Hdac4 interacts with the transcription factor (TF) JunB, facilitating the transcriptional activation of Th17 signature genes such as Il17a/f. Conversely, Hdac7 collaborates with the TF Aiolos and Smrt/Ncor1-Hdac3 corepressors to repress transcription of Th17 negative regulators, including Il2, in Th17 cell differentiation. Inhibiting Hdac4/7 through pharmacological or genetic methods effectively mitigates Th17 cell-mediated intestinal inflammation in a colitis mouse model. Our study uncovers molecular mechanisms where HDAC4 and HDAC7 function distinctively yet cooperatively in regulating ordered gene transcription during Th17 cell differentiation. These findings suggest a potential therapeutic strategy of targeting HDAC4/7 for treating Th17-related inflammatory diseases, such as ulcerative colitis.

Animals↗
PubMed2026

PDLIM4 promotes dephosphorylation of STAT transcription factors by recruiting PTP-BL and inhibits Th1, Th2, and Th17 cell differentiation.

STAT (signal transducers and activators of transcription) transcription factors are activated by tyrosine phosphorylation after cytokine stimulation and are critical for the differentiation of T-helper (Th) cells into particular Th lineage subsets. How STAT-mediated Th cell differentiation is negatively regulated, however, is not fully understood. Here, we report that PDLIM4 binds to STAT3, 4, and 6 and suppresses gene activation mediated by these STATs. PDLIM4 acts as an adaptor that recruits PTP-BL, a protein tyrosine phosphatase, through its LIM (abnormal cell lineage 11-islet 1-mechanosensory abnormal 3) domain, facilitating dephosphorylation of STAT proteins. PDLIM4-deficiency in CD4+ T cells resulted in augmented tyrosine phosphorylation of these STAT proteins and consequently enhanced Th1, Th2, and Th17 cell differentiation, suggesting that PDLIM4 regulates the differentiation of multiple lineages of Th cells by suppressing STAT signaling. We further found that a non-synonymous single-nucleotide polymorphism in PDLIM4, which causes the substitution of a glycine residue with a cysteine in the LIM domain, is associated with susceptibility to rheumatoid arthritis and Graves' disease, both of which are known to be Th17 cell-driven autoimmune diseases. Notably, PDLIM4 containing this amino acid substitution in the LIM domain showed reduced binding to PTP-BL and was therefore partially impaired in its ability to dephosphorylate STAT3 and suppress STAT3 signaling. Our findings define an essential role of PDLIM4 in negatively regulating STAT-mediated Th-cell differentiation and preventing the onset of human autoimmune diseases.

Animals↗
PubMed2006

A critical role of LFA-1 in the development of Th17 cells and induction of experimental autoimmune encephalomyelytis.

The alphaLbeta2 integrin adhesion molecule LFA-1 is believed to be involved in the migration of autoreactive T cells to the central nervous system across the endothelial blood-brain barrier in experimental autoimmune encephalomyelitis (EAE). Here, we demonstrate that the incidence and clinical scores of EAE in LFA-1-/- mice induced by the immunization with the myelin oligodendrocyte glycoprotein (MOG)-peptide antigen were significantly lower than those in wild type mice. Further studies demonstrated that lymphocytes recruitment to the draining lymph nodes (dLN) after the immunization with the MOG-peptide was severely suppressed in LFA-1-/- mice. Moreover, generation of the MOG-specific IL-17-producing helper T (Th17) cells in the dLN was impaired in LFA-1-/- mice. These results suggest that LFA-1 may play an important role for the generation of MOG-specific Th17 cells in the dLN as well as the immigration of MOG-specific naïve CD4+ T cells to the dLN.

Amino Acid Sequence↗
PubMed2025

NLRP3 and AIM2 inflammasomes exacerbate the pathogenic Th17 cell response to eggs of the helminth Schistosoma mansoni.

Infection with the helminth Schistosoma mansoni can cause exacerbated morbidity and mortality via a pathogenic host CD4 T cell-mediated immune response directed against parasite egg antigens, with T helper (Th) 17 cells playing a major role in the development of severe granulomatous hepatic immunopathology. The role of inflammasomes in intensifying disease has been reported; however, neither the types of caspases and inflammasomes involved, nor their impact on the Th17 response are known. Here we show that enhanced egg-induced IL-1β secretion and pyroptotic cell death required both caspase-1 and caspase-8 as well as NLRP3 and AIM2 inflammasome activation. Schistosome genomic DNA activated AIM2, whereas reactive oxygen species, potassium efflux and cathepsin B, were the major activators of NLRP3. NLRP3 and AIM2 deficiency led to a significant reduction in pathogenic Th17 responses, suggesting their crucial and non-redundant role in promoting inflammation. Additionally, we show that NLRP3- and AIM2-induced IL-1β suppressed IL-4 and protective Type I IFN (IFN-I) production, which further enhanced inflammation. IFN-I signaling also curbed inflammasome- mediated IL-1β production suggesting that these two antagonistic pathways shape the severity of disease. Lastly, Gasdermin D (Gsdmd) deficiency resulted in a marked decrease in egg-induced granulomatous inflammation. Our findings establish NLRP3/AIM2-Gsdmd axis as a central inducer of pathogenic Th17 responses which is counteracted by IFN-I pathway in schistosomiasis.

Animals↗
PubMed2007

T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis.

This report shows that highly self-reactive T cells produced in mice as a result of genetically altered thymic T cell selection spontaneously differentiate into interleukin (IL)-17-secreting CD4+ helper T (Th) cells (Th17 cells), which mediate an autoimmune arthritis that clinically and immunologically resembles rheumatoid arthritis (RA). The thymus-produced self-reactive T cells, which become activated in the periphery via recognition of major histocompatibility complex/self-peptide complexes, stimulate antigen-presenting cells (APCs) to secrete IL-6. APC-derived IL-6, together with T cell-derived IL-6, drives naive self-reactive T cells to differentiate into arthritogenic Th17 cells. Deficiency of either IL-17 or IL-6 completely inhibits arthritis development, whereas interferon (IFN)-gamma deficiency exacerbates it. The generation, differentiation, and persistence of arthritogenic Th17 cells per se are, however, insufficient for producing overt autoimmune arthritis. Yet overt disease is precipitated by further expansion and activation of autoimmune Th17 cells, for example, via IFN-gamma deficiency, homeostatic proliferation, or stimulation of innate immunity by microbial products. Thus, a genetically determined T cell self-reactivity forms a cytokine milieu that facilitates preferential differentiation of self-reactive T cells into Th17 cells. Extrinsic or intrinsic stimuli further expand these cells, thereby triggering autoimmune disease. Intervention in these events at cellular and molecular levels is useful to treat and prevent autoimmune disease, in particular RA.

Animals↗
PubMed2006

Mast cell-derived TNF can promote Th17 cell-dependent neutrophil recruitment in ovalbumin-challenged OTII mice.

Both mast cells and IL-17 can contribute to host defense and pathology in part by orchestrating neutrophil recruitment, but the possible role of mast cells in IL-17-induced inflammation remains to be defined. We found that mast cells and IL-17, but neither IFN-gamma nor FcRgamma signaling, contributed significantly to the antigen (Ag)-dependent airway neutrophilia elicited in ovalbumin-specific T-cell receptor (TCR)-expressing C57BL/6-OTII mice, and that IFN-gamma significantly suppressed IL-17-dependent airway neutrophilia in this setting. IL-18, IL-1beta, and TNF each contributed significantly to the development of Ag- and T helper 17 (Th17 cell)-mediated airway neutrophilia. Moreover, IL-17 enhanced mast cell TNF production in vitro, and mast cell-associated TNF contributed significantly to Ag- and Th17 cell-mediated airway neutrophilia in vivo. By contrast, we detected no significant role for the candidate mediators histamine, PGD(2), LTB(4), CXCL10, or IL-16, each of which can be produced by mast cells and other cell types, in the neutrophil infiltration elicited in this model. These findings establish that mast cells and mast cell-derived TNF can significantly enhance, by FcRgamma-independent mechanisms, the Ag- and Th17 cell-dependent development of a neutrophil-rich inflammatory response at a site of Ag challenge.

Animals↗
PubMed2006

The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.

IL-17-producing T lymphocytes have been recently shown to comprise a distinct lineage of proinflammatory T helper cells, termed Th17 cells, that are major contributors to autoimmune disease. We show here that the orphan nuclear receptor RORgammat is the key transcription factor that orchestrates the differentiation of this effector cell lineage. RORgammat induces transcription of the genes encoding IL-17 and the related cytokine IL-17F in naïve CD4(+) T helper cells and is required for their expression in response to IL-6 and TGF-beta, the cytokines known to induce IL-17. Th17 cells are constitutively present throughout the intestinal lamina propria, express RORgammat, and are absent in mice deficient for RORgammat or IL-6. Mice with RORgammat-deficient T cells have attenuated autoimmune disease and lack tissue-infiltrating Th17 cells. Together, these studies suggest that RORgammat is a key regulator of immune homeostasis and highlight its potential as a therapeutic target in inflammatory diseases.

Animals↗
PubMed2025

Effect of Chang'an decoction on ulcerative colitis by regulating T helper 17 cells and regulatory T cellsRab27 in the p53/high mobility group box 1 pathway.

OBJECTIVE: To explore the effect of Chang'an decoction (, CAD) of ameliorating the immune imbalances in ulcerative colitis (UC) by regulating Rab27 in the P53/high mobility group box 1 pathway. METHODS: The functions and important signaling pathways of the Rab27- and UC-related genes were analyzed viathe use of microarray data from the gene expression omnibus database, gene ontology database, Kyoto encyclopedia of genes and genomes database and gene set enrichment analysis. Dextran sulfate sodium salt-induced colitis mouse model was used to verify the bioinformatics results. Colon length, body weight, and disease activity index were measured. Hematoxylin and eosin staining was applied to validate the histopathology. Tight junction proteins were detected by immunohistochemistry. The proportions of T helper 17 cells (Th17) and regulatory T cells (Treg) in mesenteric lymph nodes were measured viaflow cytometry. Proinflammatory cytokines like interleukin (IL) 17 (IL-17), IL-21 and IL-22 and anti-inflammatory cytokines like transforming growth factor β and IL-10 in the serum and colon of mice were detected by enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction, respectively. The expression levels of high mobility group box 1 (HMGB1), P53 and phospho- P53 (P-P53) in colonic tissues were detected by immunofluorescence and Western blotting. RESULTS: Bioinformatics analysis revealed that compared with normal tissues, the expression of Rab27 was significantly increased in UC tissues. Receiver operating characteristic curve showed that Rab27 has the potential to be used as a biomarker for the diagnosis of disease activity. Enrichment analysis showed that UC and Rab27 were mainly associated with small molecule transport, nutrient metabolism, transmembrane transport and the downstream pathway of P53. According to animal experiments, the expression of Rab27 was increased in UC tissues, which aggravated the colonic pathological damage, activated the expression of HMGB1, and also leaded to the imbalance of Th17 and Treg cells. After CAD intervention, Rab27 overexpression, weight loss, colon shortening, and pathological damage were substantial reduced, the expression of tight junction proteins, zona occludens 1 and Occludin were increased. The effect of CAD at high-dose was more obvious. In addition, CAD upgraded the number of Treg cells and the production of TGF-β and IL-10, while decreasing the number of Th17 cells and the expression of inflammatory cytokines (IL-17, IL-21, and IL-22). Moreover, colon inflammation was alleviated by CAD, as indicated by the regulation of HMGB1 and P-P53 expression. CONCLUSION: The expression of Rab27, HMGB1 and P-P53 could be decreased by CAD, and the balance of Th17 and Treg cells as well as their related cytokines could be regulated by CAD.

Animals↗
PubMed2006

TGFbeta1, a "Jack of all trades": the link with pro-inflammatory IL-17-producing T cells.

Transforming growth factor (TGF)beta is most commonly considered an anti-inflammatory cytokine, a view that clearly does not correlate with the recently described role for TGFbeta1 in the differentiation of T-helper (Th)17 cells, a novel, highly inflammatory T-cell subset that produces interleukin (IL)-17. However, these recent findings endorse earlier studies, pre-dating the discovery of Th17 cells, which described a seemingly paradoxical pro-inflammatory role of TGFbeta. In this article, we propose that the administration of neutralizing anti-TGFbeta antibodies in target sites of chronic inflammation would ameliorate or abolish disease because this would limit the differentiation of Th17 cells. By contrast, similar interventions at mucosal sites, where Th17 cells seem to have a protective role, might exacerbate disease in experimental models of colitis. An excess production of Th17 cells in response to infection or trauma could result in leakage into peripheral tissues and cause autoimmune pathology.

Animals↗
PubMed2026

Enhanced HIF-1α cooperation by a human RORγt mutant potentiates Th17 pathogenicity.

T helper 17 (Th17) cells are pivotal in mucosal defense and autoimmune pathology, with their function governed by the transcription factor retinoic acid receptor-related orphan receptor gamma t (RORγt). Although genome-wide association studies link RORC variants to inflammatory diseases, their functional consequences remain poorly understood. We identify a pathogenic RORγt mutation N277D (mouse homolog N275D) that amplifies Th17 pathogenicity through cooperation with hypoxia-inducible factor HIF-1α. This mutation enhances IFN-γ and other Th1-type cytokine production by Th17 cells, exacerbating colitis without disrupting T cell development or homeostasis. Integrated transcriptomic and metabolomic profiling reveals activation of glycolytic and hypoxia-associated pathways, consistent with increased RORγtN275D recruitment by HIF-1α to the Pdk1 locus. Notably, silencing Pdk1 normalizes the excessive IFN-γ production in RORγtN275D Th17 cells. Together, these findings define a regulatory axis linking RORγt and HIF-1α that coordinates transcriptional and metabolic programs in pathogenic Th17 cells, providing a framework for dissecting the functional impact of autoimmune risk variants.

CP: immunology↗
PubMed2025

Altered ruminal microbiome tryptophan metabolism and their derived 3-indoleacetic acid inhibit ruminal inflammation in subacute ruminal acidosis goats.

BACKGROUND: Subacute ruminal acidosis (SARA) is a digestive disorder that often severely jeopardizes the health and lactation performance of ruminants fed a high-energy diet. Different dairy ruminants exhibit varying degrees of inflammation accompanied by variations in the rumen microbiota when SARA occurs. Our understanding of the occurrence of SARA and varying degrees of rumen epithelial inflammation is lacking. Hence, we performed rumen metagenomic, metagenome-assembled genome and metabolomic analyses, with transcriptome and single-nucleus RNA sequence analyses, to explore the microbial mechanism of SARA occurrence and different degrees of inflammation. RESULTS: A total of 36 goats fed two diets with gradually increasing levels of rumen-degradable starch (RDS) were included in this study, and SARA goats fed 70% concentrate diets supplemented with whole corn (HGW-SARA) and SARA goats fed 70% concentrate diets supplemented with crushed corn (HGC-SARA) were identified. Moreover, 11 goats fed a control basal diet, named LGW-CON, were also included. Compared with those in the LGW-CON group, the rumen fermentation capacity was enhanced, accompanied by ruminal epithelial and systemic inflammation, in goats from HGW-SARA and HGC-SARA. Between them, HGC-SARA goats presented less inflammation. Notably, the ruminal inflammation-related pathways were increased only in the HGW-SARA group but not in the HGC-SARA group. Metagenomic analysis revealed that the β diversity of SARA goats was significantly different from that of LGW-CON goats. Ruminococcus significantly increased in both SARA groups, whereas Prevotella and Bacteroidales significantly decreased, which was accompanied by a decrease in cellulose and hemicellulose enzymes and an increase in lysozymes and lipopolysaccharide synthesis enzymes. Multi-omics analysis of the ruminal contents and tissues suggested that epithelial inflammation was caused by disturbed ruminal microbiome-induced Th17 cell differentiation and IL-17 signalling pathway activation. Comparative analyses between the HGW-SARA and HGC-SARA groups highlighted the importance of Selenomonas and Bifidobacterium, as well as bacterial tryptophan metabolism, in the production of 3-indoleacetic acid, which mitigated ruminal epithelial inflammation by modulating Th17 cells and inhibiting IL-17 signalling. Ruminal microbiota transplantation from HGW-SARA goats to healthy dairy goats and mice revealed the role of microbes in epithelial inflammation. Additionally, 3-indoleacetic acid supplementation reduced rumen inflammation and the IL-17 concentration in the serum, improved VFAs absorption, and enhanced milk production. CONCLUSIONS: This study unveiled that after SARA was induced by high-concentrate feeding, the rumen homeostasis was disrupted, and rumen fiber degradation capacity of dairy goats decreased, but the LPS synthesis capacity increased, and inflammation of the rumen epithelium was observed. However, the ruminal microbial species from the Bifidobacterium and Selenomonas genera and bacterial 3-indole acetic acid are pivotal in mitigating ruminal epithelial inflammation during SARA in dairy goats. This could potentially be attributed to the modulation of ruminal Th17 cell proportions and the inhibition of IL-17 signalling pathways. Video Abstract.

Rumen↗
PubMed2006

IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx?

BACKGROUND: The role of Th2 cells (producing interleukin (IL-)4, IL-5 and IL-13) in allergic asthma is well-defined. A distinct proinflammatory T cell lineage has recently been identified, called Th17 cells, producing IL-17A, a cytokine that induces CXCL8 (IL-8) and recruits neutrophils. Neutrophilic infiltration in the airways is prominent in severe asthma exacerbations and may contribute to airway gland hypersecretion, bronchial hyper-reactivity and airway wall remodelling in asthma. AIM: to study the production of IL-17 in asthmatic airways at the mRNA level, and to correlate this with IL-8 mRNA, neutrophilic inflammation and asthma severity. METHODS: We obtained airway cells by sputum induction from healthy individuals (n = 15) and from asthmatic patients (n = 39). Neutrophils were counted on cytospins and IL-17A and IL-8 mRNA expression was quantified by real-time RT-PCR (n = 11 controls and 33 asthmatics). RESULTS: Sputum IL-17A and IL-8 mRNA levels are significantly elevated in asthma patients compared to healthy controls. IL-17 mRNA levels are significantly correlated with CD3gamma mRNA levels in asthmatic patients and mRNA levels of IL-17A and IL-8 correlated with each other and with sputum neutrophil counts. High sputum IL-8 and IL-17A mRNA levels were also found in moderate-to-severe (persistent) asthmatics on inhaled steroid treatment. CONCLUSION: The data suggest that Th17 cell infiltration in asthmatic airways links T cell activity with neutrophilic inflammation in asthma.

Adolescent↗
PubMed2006

Regulation of the T cell response.

The T cell branch of the immune system can respond to a virtually infinite variety of exogenous antigens, thus including the possibility of self-antigen recognition and dangerous autoimmune reactions. Therefore, regulatory mechanisms operate both during ontogeny within the thymus and after birth in the periphery. The control of self-reactive T cells occurs through a process of negative selection that results in apoptosis of T cells showing high affinity for self-peptides expressed at the thymic level by means of promiscuous gene expression. Self-reactive T cells escaped to negative selection are controlled in the periphery by other regulatory mechanisms, the most important being natural Foxp3+ T regulatory (Treg) cells. Regulation is also required to control excessive effector T cell responses against exogenous antigens, when they become dangerous for the body. Three types of effector T cells have been recognized: T helper 1 (Th1) cells, which are protective against intracellular bacteria; Th2 cells, which play some role in the protection against nematodes, but are responsible for allergic reactions; Th17 cells, which are probably effective in the protection against extracellular bacteria, but also play a role in the amplification of autoimmune disorders. Abnormal or excessive Th effector responses are regulated by different mechanisms. Redirection or immune deviation of Th1- or Th2-dominated responses is provided by cytokines [interferon-gamma (IFN-gamma) vs. interleukin-4 (IL-4)] produced by the same cell types and by the CXCR3-binding chemokines CXCL4 and CXCL10. Moreover, both Th1 and Th2 responses can be suppressed by adaptive Treg cells through contact-dependent mechanisms and/or the production of IL-10 and transforming growth factor-beta (TGF-beta). Finally, TGF-beta1 can promote the development of both Th17 effector and adaptive Treg cells, while the contemporaneous production of IL-6 contributes to the development of Th17 cells, but inhibits Treg cells. The development of Th17 cells is also down-regulated by IL-4 produced by Th2 cells and by IFN-gamma produced by Th1 cells.

Allergens↗
PubMed2026

A Functionally Constrained Immune Ecosystem in Microsatellite-stable Colorectal Cancer Resolved by Single-cell and Exome Profiling.

BACKGROUND/AIM: Microsatellite-stable (MSS) colorectal cancer (CRC) generally responds poorly to immune checkpoint blockade, but some MSS tumors are T-cell rich. We examined whether such infiltration reflected effective immunity or functional immune constraint. CASE REPORT: A 77-year-old woman underwent resection of a mismatch repair-proficient (pMMR), MSS, low-mutational-burden CRC with a synchronous adenoma. Whole-exome sequencing of tumor, adenoma and adjacent normal tissue detected no shared high-confidence somatic mutations between tumor and adenoma within the sensitivity of this WES analysis and identified tumor-specific APC, KRAS and TP53 alterations. Tumor single-cell RNA sequencing yielded 7,569 cells, with T-lineage populations comprising 83.5%. Cytotoxic T cells showed cytolytic and dysfunction-associated features, regulatory T cells (Tregs) showed suppressive remodeling, and Th17 cells showed inflammatory/profibrotic programs. CellChat nominated stromal MIF/FN1-CD74/CD44 and extracellular-matrix communication with T-cell compartments. CONCLUSION: This molecular case report shows that T-cell abundance and immune effectiveness can be uncoupled in MSS CRC.

Humans↗
PubMed2006

Vaccination against IL-17 suppresses autoimmune arthritis and encephalomyelitis.

Interleukin 17 is a T cell-derived cytokine that induces the release of pro-inflammatory mediators in a wide range of cell types. Recently, a subset of IL-17-producing T helper cells (Th17) distinct from Th1 and Th2 cells has been described, which constitutes a new T cell polarization state. Aberrant Th17 responses and overexpression of IL-17 have been implicated in a number of autoimmune disorders including rheumatoid arthritis and multiple sclerosis. Molecules blocking IL-17 such as IL-17-specific monoclonal antibodies have proved to be effective in ameliorating disease in animal models. Hitherto, active immunization targeting IL-17 is an untried approach. Herein we explore the potential of neutralizing IL-17 by active immunization using virus-like particles conjugated with recombinant IL-17 (IL-17-VLP). Immunization with IL-17-VLP induced high levels of anti-IL-17 antibodies thereby overcoming natural tolerance, even in the absence of added adjuvant. Mice immunized with IL-17-VLP had lower incidence of disease, slower progression to disease and reduced scores of disease severity in both collagen-induced arthritis and experimental autoimmune encephalomyelitis. Active immunization against IL-17 therefore represents a novel therapeutic approach for the treatment of chronic inflammatory diseases.

Animals↗
PubMed2026

Microplastics and nanoplastics-related genes signature predicts prognosis in pancreatic ductal adenocarcinoma and functional validation of interleukin 1 alpha.

BACKGROUND: Microplastics and nanoplastics (MNPs), as emerging environmental pollutants, have garnered significant attention from the global scientific community due to their potential threats to human health, particularly their association with the occurrence and development of cancer. The goal of our study is to create a predictive marker for pancreatic ductal adenocarcinoma (PAAD) based on MNPs-related genes, with the purposes of predicting survival outcomes and assessing the tumor immune microenvironment. METHODS: Using multi-cohort data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and International Cancer Genome Consortium (ICGC), we assessed the association between MNPs and PAAD prognosis through the Xiantao Academic (https://www.xiantao.love/). The development of a prognostic signature was followed by an assessment of its significance through the Kaplan-Meier method, time-dependent receiver operating characteristic (ROC), and decision curve analysis (DCA). The validity of the risk model was confirmed through the ICGC and GSE71729 cohorts. The model was then assessed for levels of tumor immune infiltration. To explore MNPs-related genes expression characteristics within immune cells in PAAD, we performed single-cell RNA sequencing and spatial transcriptomics analysis through the Sparkle Platform (https://grswsci.top/). Finally, in vitro experiments were conducted to investigate the biological function of interleukin 1 alpha (IL1A). RESULTS: A four-gene signature comprising XDH, IL1A, KIF20A, and ASPM, based on MNPs, was developed to stratify PAAD patients into two distinct risk groups. The high-risk group showed a significantly poorer prognosis. A similar trend was verified in the external cohorts ICGC and GSE71729. The signature risk score affected immune cell infiltration in the PAAD microenvironment. The infiltration of B cells, CD8+ T cells, cytotoxic cells, immature dendritic cells (iDCs), mast cells, plasmacytoid dendritic cell (pDC), T cells, Tem cells, T follicular helper (TFH) cells, and T helper 17 (Th17) cells had a positive correlation with the low-risk group. In contrast, high-risk patients tended to have increased number of T helper (Th2) cells and higher expression of SIGLEC15, CD274, IGSF8. Knockdown of IL1A in PAAD cells inhibited their tumor proliferation ability in vitro. CONCLUSIONS: Using MNPs-related genes, we built a prognostic model for PAAD, revealing that patients with high-risk scores are likely to have a worse prognosis. This model is designed to develop personalized treatment strategies tailored to the specific needs of each patient, thereby improving clinical outcomes for PAAD patients. Furthermore, IL1A could be a promising therapeutic candidate for PAAD.

Microplastics↗