Transcription Factor STAT3 Research Articles

Interpreting the role of epigallocatechin-3-gallate in Epstein-Barr virus infection-mediated neuronal diseases.

The increasing prevalence of neurodegenerative diseases is a formidable task due to their multifactorial causation and treatments limited to disease maintenance and progression. Epstein-Barr virus (EBV) is reported to be involved with neuropathologies; previous studies from our group suggested the effective binding of epigallocatechin-3-gallate (EGCG) with EBV nuclear antigen 1 (EBNA1) and glycoprotein H (gH). Therefore, in the current study, we evaluated the anti-EBV effect of ECGG on the neuronal cells. EBV-GFP exhibited a decline after EGCG treatment. We have observed a decrease in specific latent and lytic cycle genes. EBNA1 unravelled attenuation at day 1 (D1), whereas EBNA3B, EBNA3C, BMRF1, BZLF1, and gp350 showed major downregulation in D3 compared to EBV infection. Notably, EBNA-LP has shown mitigation in both the considered time points. Inflammatory and chemokine moieties like IL-6, CCR1, CCR3, and CCR5 declined upon EGCG treatment, while IL-10 exhibited elevation. Transcription factor STAT3 and NF-kB were decreased, especially in the pre-EGCG treated samples. Subsequently, restoration in the mitochondrial membrane potential was observed after EGCG treatment. We observed an increase in the mitochondrial fission genes like DRP1 and MiD49, and not many regulations were observed in the mitochondrial fusion genes except MFN2. Furthermore, the CytC, CytC oxidase, MAVS, ANT, and SDH exhibited elevation upon EGCG treatment, while ATPsyn and ABAD showed downregulation. Dysfunction of mitochondria is further related to apoptosis of neurons. Herein, we were keen to examine the level of amyloid-precursor protein (APP), and it has also indicated declined after EGCG treatment. Altogether, the current study demonstrated the anti-EBV effect of EGCG by subsiding the EBV-mediated inflammation and amendments in the neuropathological markers.

Matrix-Rigidity Cooperates With Biochemical Cues in M2 Macrophage Activation Through Increased Nuclear Deformation and Chromatin Accessibility.

Macrophages encounter a myriad of biochemical and mechanical stimuli across various tissues and pathological contexts. Notably, matrix rigidity has emerged as a pivotal regulator of macrophage activation through mechanotransduction. However, the precise mechanisms underlying the interplay between mechanical and biochemical cues within the nuclear milieu remain elusive. Here We elucidate how the increased matrix rigidity drives macrophages to amplify alternatively-activated (M2 phenotype) signaling cooperatively with biochemical cues (e.g., IL4/13) through altered nuclear mechanics. We demonstrate that reconstructed podosome-like F-actins and contractility induce nucleus deformation, opening nuclear pores, which facilitates nuclear translocation of the key transcription factor STAT6. Furthermore, the altered nuclear mechanics increases chromatin accessibility induced by H3K9 methylation, particularly of M2-associated gene promoters. These cooperative events of the mechano-chemical signaling at the cytoskeletal-to-nuclear domains facilitate M2 transcriptional activation and cellular functions. We further evidence the rigidity-primed M2 macrophages are immunosuppressive and accumulated within stiffened tumors in patients. This study proposes a mechanism by which matrix mechanics crosstalks with biochemical signals to potentiate macrophage activation through nuclear mechanosensing and chromatin modifications, offering insights into macrophage mechanobiology and its therapeutic modulations.

Degrading Mutant IDH1 Employing a PROTAC-Based Approach Impairs STAT3 Activation.

Heterozygous mutations in IDH1 (isocitrate dehydrogenase 1) are found in most grade II and III brain tumors. A slew of mutant IDH1 inhibitors were identified soon after the discovery of IDH1 mutations in brain tumors. But recent reports show that mutant IDH1 inhibitors reverse therapeutic vulnerabilities and activate the oncogenic transcription factor STAT3 in mutant IDH1-expressing cells. Thus, inhibiting mutant IDH1 using mutant IDH1-specific inhibitors can result in drug resistance. Therefore, to block mutant IDH1, it is imperative to identify alternative modes of therapy. In these lines, recent findings show that PROteolysis TArgeting Chimera (PROTAC) molecules can be designed to degrade target proteins in cancer cells. However, it is unknown whether degrading mutant IDH1 leads to STAT3 activation. Therefore, in this study, we asked if degrading mutant IDH1 by employing a PROTAC-based approach leads to STAT3 activation. To answer the question, we adopted the dTAG system, where we fused FKBP12F36V to mutant IDH1 proteins and used the FKBP12F36V-specific PROTAC, dTAG-13, to degrade mutant IDH1-FKBP12F36V. We assessed STAT3 activation in dTAG-13-treated cells expressing mutant IDH1-FKBP12F36V. We found that fusing FKBP12F36V-HA to mutant IDH1 phenocopies mutant IDH1 with similar expression levels, enzyme activity, and cellular localization. We observed that dTAG-13 degrades mutant IDH1-FKBP12F36V-HA in a dose- and time-responsive manner. Unlike inhibiting, degrading mutant IDH1-FKBP12F36V-HA did not lead to pSTAT3-Y705 activation. We conclude that degrading mutant IDH1 by employing a PROTAC-based approach impairs STAT3 activation. Based on these observations, we suggest that mutant IDH1-specific PROTACs can be developed to degrade mutant IDH1 in gliomas.

Taking a Swing at TIMP1-Armed Immunosuppressive Astrocytes Unleashes T cell Immunity against Brain Metastases.

Priego and colleagues identify a secreted glycoprotein TIMP1, expressed downstream of the transcription factor STAT3, in a subpopulation of STAT3+ reactive astrocytes as a mediator of immunosuppression in late-stage brain metastases. The STAT3 inhibitor silibinin enhances the preclinical efficacy of the combined PD-1/CTLA4 immune checkpoint blockade, providing a rationale to translate the combination therapy into clinical use for this underserved patient group with poor prognosis. See related article by Priego et al., p. 179.

LncRNA NORAD modulates STAT3/STAT1 balance and innate immune responses in human cells via interaction with STAT3

Long non-coding RNAs (lncRNAs) are pivotal regulators of cellular processes. Here we reveal an interaction between the lncRNA NORAD, noted for its role in DNA stability, and the immune related transcription factor STAT3 in embryonic and differentiated human cells. Results from NORAD knockdown experiments implicate NORAD in facilitating STAT3 nuclear localization and suppressing antiviral gene activation. In NORAD-deficient cells, STAT3 remains cytoplasmic, allowing STAT1 to enhance antiviral activity. Analysis of RNA expression data from in vitro experiments and clinical samples demonstrates reduced NORAD upon viral infection. Additionally, evolutionary conservation analysis suggests that this regulatory function of NORAD is restricted to humans, potentially owing to the introduction of an Alu element in hominoids. Our findings thus suggest that NORAD functions as a modulator of STAT3-mediated immune suppression, adding to the understanding of lncRNAs in immune regulation and evolutionary adaptation in host defense mechanisms.

The C3/C3aR pathway exacerbates acetaminophen-induced mouse liver injury via upregulating podoplanin on the macrophage.

Acute liver failure (ALF) is a life-threatening condition that occurs when the liver sustains severe damage and rapidly loses its function. The primary cause of ALF is the overdose of acetaminophen (APAP), and its treatment is relatively limited. The involvement of the complement system in the development of ALF has been implicated. However, the related mechanisms remain poorly understood. Complement 3 (C3) knockout mice, complement 3a receptor (C3aR) knockout mice, platelet C-type lectin-like receptor 2 (Clec-2)-deficient mice, and myeloid cell podoplanin (Pdpn)-deficient mice were generated. Liver tissues were collected for histological analysis, RNA sequencing, confocal immunofluorescence, and immunoblot analyses. Our data demonstrated that APAP activated the C3/C3aR pathway, leading to intrahepatic hemorrhage, ultimately resulting in hepatocyte necrosis. Deletion of C3 or C3aR mitigated APAP-induced liver injury (AILI). C3/C3aR signaling upregulated the expression and phosphorylation of transcription factors STAT3 and c-Fos in hepatic Kupffer cells, which in turn increased PDPN expression, promoting platelet recruitment to the Kupffer cells via the interaction of PDPN and the CLEC-2 on platelets. Since the activation of platelets mediated by C3/C3aR occurs irrespective of the major hemostatic pathways, blocking the C3/C3aR pathway in ALF could be a coagulopathy-sparing and novel therapeutic approach. In summary, this study unveiled the critical roles of the C3/C3aR pathway in developing AILI, providing evidence that the C3/C3aR pathway could be an effective therapeutic target for AILI.

The Impact of Cell-Intrinsic STAT6 Protein on Donor T Cell-Mediated Graft-Versus-Tumor Effect.

Bone marrow transplantation (BMT) is mainly performed to restore an anti-tumor immune response, called the graft-versus-tumor (GVT) effect, against leukemia, myeloma and lymphoma. This GVT reactivity is driven by donor T cells, and it can also cause lethal graft-versus-host disease (GVHD). We previously demonstrated that the colonization of mice with helminths preserves the GVT response while suppressing GVHD. As the T helper-2 (Th2) pathway is critical to helminthic immune regulation, we asked whether the genetic induction of Th2 signaling in donor T cells can restore helminthic immune regulation after BMT. Our studies utilized transgenic donor T lymphocytes that overexpress a constitutively active form of the Th2-associated transcription factor STAT6. Constitutively active STAT6 sustained the GVT response without causing severe acute GVHD, where transgenic T cells generated robust quantities of cytotoxic proteins important in GVT response, such as granzymes A and B, interferon-γ and Fas ligand, in addition to generating high quantities of Th2/regulatory cytokines. Bioinformatic analysis based on chromosome immune precipitation experiments indicated that STAT6 stimulates the expression of granzymes directly. Thus, in preserving the GVT response without causing GVHD mortality, our results indicate the therapeutic potential of restoring helminthic immune modulation by targeting STAT6 and STAT6-dependent T cell maturation.

Low Renalase Levels in Newly Diagnosed CML: Dysregulation Sensitive to Modulation by Tyrosine Kinase Inhibitors.

Background: A dysregulated proinflammatory microenvironment is considered one of the reasons why current therapies of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKI) do not secure disease control. Therefore, the development of BCR-ABL1-independent therapies is encouraged. Renalase (RNLS) is a multifunctional protein that exhibits both enzymatic and non-enzymatic cytokine-like properties, along with potent anti-inflammatory and anti-apoptotic effects. It is expressed in various tissues, including tumors. Methods: We investigated the levels of RNLS in the blood of CML patients in the chronic phase, treatment naïve patients, and those in remission under TKI treatment (either imatinib or nilotinib) and compared them to healthy individuals. Results: Renalase concentration was markedly decreased in treatment-naive CML patients compared to other groups (p = 0.000), while lower levels in the TKI group were not statistically significant compared to controls. The levels correlated negatively with the total leukocyte and neutrophil count (p < 0.05), while a positive correlation was present with CRP levels in treatment naïve patients. Conclusions: Dynamic regulation of RNLS expression and activity is coupled with transcription factors NF-κB and STAT3. Interpretation of our results might rely on differential requirements of activated STATs (STAT3/5) during CML clone development and maintenance, including the observation of RNLS rise upon TKI introduction. Overall, our research provides new insights into the field of hematological malignancies. Unlike other malignancies studied, RNLS plasma levels are significantly decreased in CML. In future perspectives, RNLS could potentially serve as a diagnostic, prognostic, or therapeutic option for these patients.

Muramyl dipeptide potentiates Staphylococcus aureus lipoteichoic acid-induced nitric oxide production via TLR2/NOD2/PAFR signaling pathways.

Lipoteichoic acid (LTA) and peptidoglycan (PGN) are considered as key virulence factors of Staphylococcus aureus, which is a representative sepsis-causing Gram-positive pathogen. However, cooperative effect of S. aureus LTA and PGN on nitric oxide (NO) production is still unclear despite the pivotal roles of NO in initiation and progression of sepsis. We here evaluated the cooperative effects of S. aureus LTA (SaLTA) and muramyl dipeptide (MDP), the minimal structure of PGN, on NO production in both a mouse macrophage-like cell line, RAW 264.7 and mouse bone marrow-derived macrophages (BMMs). Although MDP alone did not affect NO production, MDP potently enhanced SaLTA-induced NO production via the expression of inducible NO synthases. The enhanced NO production was ameliorated in BMMs from TLR2-, CD14-, MyD88-, and NOD2-deficient mice. Moreover, the augmented SaLTA-induced NO production by MDP was attenuated by inhibitors specific for PAFR and MAP kinases. Furthermore, MDP also potently increased SaLTA-induced activities of STAT1, NF-κB, and AP-1 transcription factors, and specific inhibitors for these transcription factors suppressed the elevated NO production. Collectively, these results demonstrated that MDP potentiates SaLTA-induced NO production via TLR2/NOD2/PAFR, MAP kinases signaling axis, resulting in the activation of NF-κB, AP-1 and STAT1 transcription factors.

Exploring sex-specific genetic architecture of coronary artery disease in Tehran: a cardiometabolic genetic study

ABSTRACT Background The development of coronary artery disease (CAD) is influenced by sex and genetic factors. Genome-wide association studies (GWAS) have linked genetic loci to CAD, mostly in European populations. The study aims to find sex-related genetic differences in the Iranian population. Research design and methods We conducted a sex-stratified GWAS with 4519 subjects (1832 males and 2687 females) in the discovery group and 922 subjects (495 males and 427 females) in the confirmation group of an Iranian cohort. We analyzed 9,141,124 variants using a genome-wide complex trait analysis (GCTA) tool. Results We detected distinct genetic variants associated with CAD in males: rs34952209 [OR = 1.79; p = 5.216E–8], rs1432687863 [OR = 1.95; p = 8.477E–8], and in females, rs7314741 [OR = 1.67; p = 7.142-8E] positively influenced CAD risk. The CAD-associated SNPs that were obtained have been confirmed using independent samples. Rs3495229 May impact histone mark and Pou2f2 motifs, while rs7314741 in the LEM Domain Containing 3 (LEMD3) promoter may affect a regulatory motif for the STAT transcription factor. According to Roadmap and ENCODE data, Rs1432687863 is a new variant affecting CAD in males, potentially through H3K9me3 in the heart. Conclusions Our findings highlight the role of sex-specific genetic differences in CAD development, providing novel insights into disease pathways which is not appropriate using a sex-combined strategy.

Reduced thymic IL-4 impairs negative T cell selection in nonobese diabetic mice.

Type 1 diabetes (T1D) develops spontaneously despite functional antigen presentation machinery in the thymus and a perceptible central tolerance process. We found that intrathymic enrichment with IL-4 fine tunes signaling through the IL-4/IL-13 heteroreceptor (HR) in early thymic progenitors (ETPs), augments negative selection of self-reactive T cells, sustains a diverse T cell repertoire devoid of clones expressing disease-associated T cell receptor (TCR) genes, and protects the nonobese diabetic (NOD) mouse from T1D. Indeed, optimal IL-4 activates STAT transcription factors to program ETP fate decision toward CD11c+CD8α+ dendritic cells (DCs) agile in negative T cell selection and clonal deletion of diabetogenic T cells. However, due to diminished invariant natural killer T (iNKT) 2 cell frequency in the NOD thymus, IL-4 is as suboptimal level, metering STAT activation to program ETP fate decision toward the T cell lineage leading to diminished negative selection, a clonally restricted TCR repertoire, and manifestation of spontaneous T1D. These insights uncover yet another interplay by which IL-4 affects T1D.

Guben Kechuan granule attenuates bronchial asthma by inhibiting NF-κB/STAT3 signaling pathway-mediated apoptosis.

Chronic asthma caused by allergies is a lung illness marked by airway remodeling and hyperresponsiveness. Guben Kechuan (GK) granule is a clinically proven formula for treating lung disease. It relieves cough and helps to clear phlegm, but the mechanisms underlying its treatment for asthma are not clear. We aimed to elucidate the efficacy and potential mechanisms by which GK ameliorates allergic asthma. Ultra-performance liquid chromatography (UHPLC-LTQ-Orbitrap-MS) identified the main chemical components of GK. The efficacy of GK was studied in an ovalbumin/alum (OVA)/AL(OH)3-sensitized rat model of bronchial asthma by measuring cytokine concentrations in serum and alveolar lavage samples, examining tissue pathology, and performing leukocyte counts. The mechanisms underlying its effectiveness in asthma were investigated by both transcriptomic and proteomic analyses. GK relieved asthma-induced airway inflammation and remodeling, reduced inflammatory cell infiltration, and decreased the levels of the inflammatory cytokines TNF-α, IL-4, IL-5, IL-6, and IL-10. Analysis of the transcriptomic and proteomic results found that asthma activated the transcription factors STAT3 and NF-κB and induced oxidative-stress damage and apoptosis. GK was found to reduce Bax and caspase-3 expression, increase Bcl-2 expression, and inhibit asthma-induced apoptosis. GK downregulated the expression of the transcription factors STAT3 and NF-kB, which decreased the inflammatory response. Decreases in CAT, SOD, and GSH reduced asthma-induced oxidative-stress damage. Our findings provide evidence that GK alleviates bronchial asthma by inhibiting apoptosis and oxidative stress damage mediated by the NF-κB/STAT3 signaling pathway.

The intersection of endocrine signaling and neuroimmune communication regulates muscle inflammation-induced nociception in neonatal mice.

Neonatal pain is a significant clinical issue but the mechanisms by which pain is produced early in life are poorly understood. Our recent work has linked the transcription factor serum response factor downstream of local growth hormone (GH) signaling to incision-related hypersensitivity in neonates. However, it remains unclear if similar mechanisms contribute to inflammatory pain in neonates. We found that local GH treatment inhibited neonatal inflammatory myalgia but appeared to do so through a unique signal transducer and activator of transcription (STAT) dependent pathway within sensory neurons. The STAT1 transcription factor appeared to regulate peripheral inflammation itself by modulation of monocyte chemoattractant protein 1/C-C motif chemokine ligand 2 (MCP1/CCL2) release from sensory neurons. Data suggests that STAT1 upregulation, downstream of GH signaling, contributes to neonatal nociception during muscle inflammation through a novel neuroimmune loop involving chemokine release from primary afferents. Results could uncover new ways to treat muscle pain and inflammation in neonates.

Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma.

The transcription factors STAT3, STAT5A, and STAT5B steer hematopoiesis and immunity, but their enhanced expression and activation promote acute myeloid leukemia (AML) or natural killer/T cell lymphoma (NKCL). Current therapeutic strategies focus on blocking upstream tyrosine kinases to inhibit STAT3/5, but these kinase blockers are not selective against STAT3/5 activation and frequent resistance causes relapse, emphasizing the need for targeted drugs. We evaluated the efficacy of JPX-0700 and JPX-0750 as dual STAT3/5 binding inhibitors promoting protein degradation. JPX-0700/-0750 decreased the mRNA and protein levels of STAT3/5 targets involved in cancer survival, metabolism, and cell cycle progression, exhibiting nanomolar to low micromolar efficacy. They induced cell death and growth arrest in both AML/NKCL cell lines and primary AML patient blasts. We found that both AML/NKCL cells hijack STAT3/5 signaling through either upstream activating mutations in kinases, activating mutations in STAT3, mutational loss of negative STAT regulators, or genetic gains in anti-apoptotic, pro-proliferative, or epigenetic-modifying STAT3/5 targets. This emphasizes a vicious cycle for proliferation and survival through STAT3/5. Both JPX-0700/-0750 treatment reduced leukemic cell growth in human AML or NKCL xenograft mouse models significantly, being well tolerated by mice. Synergistic cell death was induced upon combinatorial use with approved chemotherapeutics in AML/NKCL cells.

8-Oxoguanine DNA Glycosylase 1 Recruits Transcription Factor STAT1 to Promote the Inflammatory Responses in Sickle Cell Disease

8-Oxoguanine DNA Glycosylase 1 Recruits Transcription Factor STAT1 to Promote the Inflammatory Responses in Sickle Cell Disease

FOXO1-mediated nuclear sequestration of STAT3 and AKT1 triggers FOXO3-dependent autophagic death in hypoxic granulosa cells.

FOXO proteins, especially FOXO1 and FOXO3, are recognized for their roles in controlling apoptosis and autophagy. Both apoptosis and autophagy have been induced in granulosa cells (GCs) by hypoxic conditions in ovarian follicles; however, the exact contribution of FOXO proteins and autophagy to the regulation of GCs apoptosis under hypoxia remains unclear. In this investigation of porcine GCs, we reveal that FOXO1 promotes apoptosis in response to hypoxia through FOXO3-dependent autophagy. We describe how mechanistically, FOXO1 forms a complex with the transcription factor STAT3 during hypoxia. Guided by FOXO1, this complex undergoes nuclear translocation and effectively attaches to the STAT3-responsive element (SRE) located in the FOXO3 promoter region, thereby enhancing the transcriptional expression of FOXO3. Simultaneously, FOXO1 associates with AKT1, thus facilitating its nuclear entry and subsequently reducing the Ser253 phosphorylation of FOXO3, leading to FOXO3 detachment from 14-3-3 and promoting FOXO3 translocation into the nucleus. FOXO3 subsequently stimulates the upregulation of ATG3, ultimately initiating autophagy and autophagy-dependent apoptosis. Our results suggest that hypoxia acts through FOXO1 to induce autophagic death in porcine GCs by promoting the expression and nuclear import of FOXO3.

LncRNA HAGLROS: A Vital Oncogenic Propellant in Various Human Cancers.

HAGLR Opposite Strand lncRNA (HAGLROS) is a long non-coding RNA (lncRNA) located on the long arm of human chromosome 2 at locus 2q31.1. Emerging evidence highlights HAGLROS as a pivotal player in human cancers, characterized by its significant upregulation across multiple malignancies where it functions as an oncogenic driver. Its aberrant expression is closely linked to the initiation and progression of 13 distinct cancer types, notably correlating with adverse clinical outcomes and reduced overall survival rates in 9 of these cancer types. Mechanistically, HAGLROS is under the regulatory influence of the transcription factor STAT3, exerts competitive binding to 9 miRNAs, activates 5 signaling pathways pivotal for cancer cell proliferation and metastasis, as well as intricately modulates gene expression profiles. Given its multifaceted roles, HAGLROS emerges as a promising candidate for cancer diagnostics and prognostics. Moreover, its potential as a therapeutic target holds considerable promise for novel treatment strategies in oncology. This review synthesizes current research on HAGLROS, covering its expression patterns, biological roles, and clinical significance in cancer. By shedding light on these aspects, this review aims to contribute new perspectives that advance our understanding of cancer biology, enhance diagnostic accuracy, refine prognostic assessments, and pave the way for targeted therapeutic interventions.

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.

Combination of proviral and antiviral roles of B cell-intrinsic STAT1 expression defines parameters of chronic gammaherpesvirus infection.

Gammaherpesviruses are species-specific, ubiquitous pathogens that establish lifelong infection in their hosts and are associated with cancers, including B cell lymphomas. Type I and II interferons (IFNs) are critical for the control of acute and chronic gammaherpesvirus infection. However, the cell type-specific role of IFN signaling during natural infection is poorly defined and is masked by the altered viral pathogenesis observed in hosts with global IFN deficiencies. STAT1 is a constitutively expressed transcription factor that is critical for the effector function of type I and II IFNs. In this study, we defined the impact of B cell-specific STAT1 expression on gammaherpesvirus infection using murine gammaherpesvirus 68 (MHV68). While the acute stage of MHV68 infection was not affected, we found opposite, anatomic site-dependent effects of B cell-intrinsic STAT1 expression during chronic infection. Consistent with the antiviral role of STAT1, B cell-specific STAT1 expression attenuated the latent viral reservoir in peritoneal B cells of chronically infected mice. In contrast, STAT1 expression in splenic B cells supported the establishment of the latent MHV68 reservoir in germinal center B cells, revealing an unexpected proviral role of B cell-intrinsic STAT1 expression during chronic gammaherpesvirus infection. These STAT1-dependent MHV68 chronic infection phenotypes were fully recapitulated in the peritoneal cavity but not the spleen of mice with B cell-specific deficiency of type I IFN receptor. In summary, our study uncovers the intriguing combination of proviral and antiviral roles of B cell-intrinsic STAT1 expression during chronic gammaherpesvirus infection.IMPORTANCEInterferons (IFNs) execute broadly antiviral roles during acute and chronic viral infections. The constitutively expressed transcription factor STAT1 is a critical downstream effector of IFN signaling. Our studies demonstrate that B cell-intrinsic STAT1 expression has opposing and anatomic site-dependent roles during chronic gammaherpesvirus infection. Specifically, B cell-intrinsic STAT1 expression restricted gammaherpesvirus latent reservoir in the peritoneal cavity, consistent with the classical antiviral role of STAT1. In contrast, decreased STAT1 expression in splenic B cells led to the attenuated establishment of gammaherpesvirus latency and decreased latent infection of germinal center B cells, highlighting a novel proviral role of B cell-intrinsic STAT1 expression during chronic infection with a B cell-tropic gammaherpesvirus. Interestingly, B cell-specific type I IFN receptor deficiency primarily recapitulated the antiviral role of B cell-intrinsic STAT1 expression, suggesting the compensatory function of B cell-intrinsic type II IFN signaling or an IFN-independent proviral role of B cell-intrinsic STAT1 expression during chronic gammaherpesvirus infection.

MALAT1/miR-582-5p/GALNT1/MUC1 axis modulates progression of AML leukemia stem cells by regulating JAK2/STAT3 pathway.

Acute myeloid leukemia (AML) is characterized by uncontrolled clonal expansion and differentiation block of immature myeloid cells. Some studies have shown that leukemia stem cells (LSC) are thought to be responsible for the initiation and development of leukemia. Moreover, abnormal O-glycosylation is a key modification in the process of cancer malignancy. In this study, GALNT1 expression was significantly upregulated in LSCs, while knockdown of GALNT1 inhibited cell viability and promoted apoptosis. Importantly, GALNT1 was the direct target of miR-582-5P, and MALAT1 directly interacted with miR-582-5P. In addition, Our investigation corroborated that MALAT1 functioned as an endogenous sponge of miR-582-5P to regulate mucin1 (MUC1) expression, catalyzed by GALNT1, which modulated the activity of JAK2/STAT3 pathway. MALAT1 and MUC1 were targets of transcription factor STAT3 and were regulated by STAT3. In general, these new findings indicated that MALAT1/miR-582-5P/GALNT1 axis is involved in the progression of LSCs, illuminating the possible mechanism mediated by O-glycosylated MUC1 via JAK2/STAT3 pathway.