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Nature Immunology May 2024Intestinal immune responses to microbes are controlled by the cytokine IL-10 to avoid immune pathology. Here, we use single-cell RNA sequencing of colon lamina propria...
Intestinal immune responses to microbes are controlled by the cytokine IL-10 to avoid immune pathology. Here, we use single-cell RNA sequencing of colon lamina propria leukocytes (LPLs) along with RNA-seq and ATAC-seq of purified CD4 T cells to show that the transcription factors Blimp-1 (encoded by Prdm1) and c-Maf co-dominantly regulate Il10 while negatively regulating proinflammatory cytokines in effector T cells. Double-deficient Prdm1MafCd4 mice infected with Helicobacter hepaticus developed severe colitis with an increase in T1/NK/ILC1 effector genes in LPLs, while Prdm1Cd4 and MafCd4 mice exhibited moderate pathology and a less-marked type 1 effector response. LPLs from infected MafCd4 mice had increased type 17 responses with increased Il17a and Il22 expression and an increase in granulocytes and myeloid cell numbers, resulting in increased T cell-myeloid-neutrophil interactions. Genes over-expressed in human inflammatory bowel disease showed differential expression in LPLs from infected mice in the absence of Prdm1 or Maf, revealing potential mechanisms of human disease.
Topics: Animals; Positive Regulatory Domain I-Binding Factor 1; Mice; Proto-Oncogene Proteins c-maf; Colitis; Mice, Knockout; Humans; Helicobacter hepaticus; Helicobacter Infections; Mice, Inbred C57BL; Intestinal Mucosa; Inflammatory Bowel Diseases; Gene Expression Regulation; Disease Models, Animal
PubMed: 38609547
DOI: 10.1038/s41590-024-01814-z -
Nature Communications Apr 2024Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease for which better therapies are urgently needed. Fibroblasts and macrophages are heterogeneous cell...
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease for which better therapies are urgently needed. Fibroblasts and macrophages are heterogeneous cell populations able to enhance metastasis, but the role of a macrophage-fibroblast crosstalk in regulating their pro-metastatic functions remains poorly understood. Here we deconvolve how macrophages regulate metastasis-associated fibroblast (MAF) heterogeneity in the liver. We identify three functionally distinct MAF populations, among which the generation of pro-metastatic and immunoregulatory myofibroblastic-MAFs (myMAFs) critically depends on macrophages. Mechanistically, myMAFs are induced through a STAT3-dependent mechanism driven by macrophage-derived progranulin and cancer cell-secreted leukaemia inhibitory factor (LIF). In a reciprocal manner, myMAF secreted osteopontin promotes an immunosuppressive macrophage phenotype resulting in the inhibition of cytotoxic T cell functions. Pharmacological blockade of STAT3 or myMAF-specific genetic depletion of STAT3 restores an anti-tumour immune response and reduces metastases. Our findings provide molecular insights into the complex macrophage-fibroblast interactions in tumours and reveal potential targets to inhibit PDAC liver metastasis.
Topics: Pancreatic Neoplasms; Animals; Liver Neoplasms; STAT3 Transcription Factor; Macrophages; Carcinoma, Pancreatic Ductal; Humans; Mice; Cell Line, Tumor; Signal Transduction; Janus Kinases; Mice, Inbred C57BL; Fibroblasts; Male; Cancer-Associated Fibroblasts; Female
PubMed: 38678021
DOI: 10.1038/s41467-024-47949-3 -
Journal of Clinical Medicine Dec 2023Histamine intolerance arises when there is a disparity between the production of histamine and the body's ability to break it down. In the gastrointestinal tract, the...
Histamine intolerance arises when there is a disparity between the production of histamine and the body's ability to break it down. In the gastrointestinal tract, the primary enzyme responsible for metabolizing ingested histamine is diamine oxidase (DAO), and a shortage of this enzyme has been associated with some diseases related to the respiratory, cardiovascular, nervous, muscular, and digestive systems, in addition to migraines. The treatment of migraines typically revolves around the utilization of both anti-migraine and anti-inflammatory drugs, but their interaction with DAO is not thoroughly understood. In this study, we examined the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) and anti-migraine medications on DAO activity through in vitro experiments. We also investigated their effects on the human intestinal cell line Caco-2, assessing changes in DAO expression (both at the mRNA and protein levels) as well as DAO activity. The tested drugs, including ibuprofen, acetylsalicylic acid, paracetamol, a combination of acetylsalicylic acid with paracetamol and caffeine, zolmitriptan, and sumatriptan, did not inhibit DAO activity or reduce their levels. However, naproxen reduced DAO protein levels in human enterocyte cultures while not affecting DAO activity. These results suggest that combining anti-inflammatory and anti-migraine drugs with DAO enzyme supplementation for migraine patients with DAO deficiency could be beneficial for healthcare professionals in their daily practice.
PubMed: 38068554
DOI: 10.3390/jcm12237502 -
Frontiers in Immunology 2023Infection-induced T cell responses must be properly tempered and terminated to prevent immuno-pathology. Using transgenic mice, we demonstrate that T cell intrinsic...
Infection-induced T cell responses must be properly tempered and terminated to prevent immuno-pathology. Using transgenic mice, we demonstrate that T cell intrinsic STAT1 signaling is required to curb inflammation during acute infection with . Specifically, we report that mice lacking STAT1 selectively in T cells expel parasites but ultimately succumb to lethal immuno-pathology characterized by aberrant Th1-type responses with reduced IL-10 and increased IL-13 production. We also find that, unlike STAT1, STAT3 is not required for induction of IL-10 or suppression of IL-13 during acute toxoplasmosis. Each of these findings was confirmed and ChIP-seq data mining showed that STAT1 and STAT3 co-localize at the locus, as well as loci encoding other transcription factors that regulate IL-10 production, most notably and . These data advance basic understanding of how infection-induced T cell responses are managed to prevent immuno-pathology and provide specific insights on the anti-inflammatory properties of STAT1, highlighting its role in shaping the character of Th1-type responses.
PubMed: 37559725
DOI: 10.3389/fimmu.2023.1212190 -
Wellcome Open Research 2023CD4 Th1 cells producing IFN-γ are required to eradicate intracellular pathogens, however if uncontrolled these cells can cause immunopathology. The cytokine IL-10 is...
BACKGROUND
CD4 Th1 cells producing IFN-γ are required to eradicate intracellular pathogens, however if uncontrolled these cells can cause immunopathology. The cytokine IL-10 is produced by multiple immune cells including Th1 cells during infection and regulates the immune response to minimise collateral host damage. In this study we aimed to elucidate the transcriptional network of genes controlling the expression of and proinflammatory cytokines, including in Th1 cells differentiated from mouse naive CD4 T cells.
METHODS
We applied computational analysis of gene regulation derived from temporal profiling of gene expression clusters obtained from bulk RNA sequencing (RNA-seq) of flow cytometry sorted naïve CD4 T cells from mouse spleens differentiated into Th1 effector cells with IL-12 and IL-27 to produce and compared to IL-27 alone which express only or IL-12 alone which express and no or medium control driven-CD4 T cells which do not express effector cytokines Data were integrated with analysis of active genomic regions from these T cells using an assay for transposase-accessible chromatin with sequencing (ATAC)-seq, integrated with literature derived-Chromatin-immunoprecipitation (ChIP)-seq data and the RNA-seq data, to elucidate the transcriptional network of genes controlling expression of and pro-inflammatory effector genes in Th1 cells. The co-dominant role for the transcription factors, (encoding Blimp-1) and (encoding c-Maf) in cytokine gene regulation in Th1 cells, was confirmed using T cells obtained from mice with T-cell specific deletion of these transcription factors.
RESULTS
We show that the transcription factors Blimp-1 and c-Maf each have unique and common effects on cytokine gene regulation and not only co-operate to induce gene expression in IL-12 plus IL-27 differentiated mouse Th1 cells, but additionally directly negatively regulate key proinflammatory cytokines including , thus providing mechanisms for reinforcement of regulated Th1 cell responses.
CONCLUSIONS
These data show that Blimp-1 and c-Maf positively and negatively regulate a network of both unique and common anti-inflammatory and pro-inflammatory genes to reinforce a Th1 response in mice that will eradicate pathogens with minimum immunopathology.
PubMed: 38074197
DOI: 10.12688/wellcomeopenres.19680.2 -
International Journal of Molecular... Sep 2023As a metastasis-prone malignancy, the metastatic form and location of melanoma seriously affect its prognosis. Although effective surgical methods and targeted drugs are...
As a metastasis-prone malignancy, the metastatic form and location of melanoma seriously affect its prognosis. Although effective surgical methods and targeted drugs are available to enable the treatment of carcinoma in situ, for metastatic tumors, the diagnosis, prognosis assessment and development of immunotherapy are still pending. This study aims to integrate multiple bioinformatics approaches to identify immune-related molecular targets viable for the treatment and prognostic assessment of metastatic melanoma, thus providing new strategies for its use as an immunotherapy. Immunoinfiltration analysis revealed that M1-type macrophages have significant infiltration differences in melanoma development and metastasis. In total, 349 genes differentially expressed in M1-type macrophages and M2-type macrophages were extracted from the MSigDB database. Then we derived an intersection of these genes and 1111 melanoma metastasis-related genes from the GEO database, and 31 intersected genes identified as melanoma macrophage immunomarkers (MMIMs) were obtained. Based on MMIMs, a risk model was constructed using the Lasso algorithm and regression analysis, which contained 10 genes (NMI, SNTB2, SLC1A4, PDE4B, CLEC2B, IFI27, COL1A2, MAF, LAMP3 and CCDC69). Patients with high+ risk scores calculated via the model have low levels of infiltration by CD8 T cells and macrophages, which implies a poor prognosis for patients with metastatic cancer. DCA decision and nomogram curves verify the high sensitivity and specificity of this model for metastatic cancer patients. In addition, 28 miRNAs, 90 transcription factors and 29 potential drugs were predicted by targeting the 10 MMIMs derived from this model. Overall, we developed and validated immune-related prognostic models, which accurately reflected the prognostic and immune infiltration characteristics of patients with melanoma metastasis. The 10 MMIMs may also be prospective targets for immunotherapy.
Topics: Humans; CD8-Positive T-Lymphocytes; Melanoma; Neoplasms, Second Primary; MicroRNAs
PubMed: 37762054
DOI: 10.3390/ijms241813752 -
Research (Washington, D.C.) 2023Solid tumor cells live in a highly dynamic mechanical microenvironment. How the extracellular-matrix-generated mechanotransduction regulates tumor cell development and...
Solid tumor cells live in a highly dynamic mechanical microenvironment. How the extracellular-matrix-generated mechanotransduction regulates tumor cell development and differentiation remains an enigma. Here, we show that a low mechanical force generated from the soft matrix induces dedifferentiation of moderately stiff tumor cells to soft stem-cell-like cells. Mechanistically, integrin β8 was identified to transduce mechano-signaling to trigger tumor cell dedifferentiation by recruiting RhoGDI1 to inactivate RhoA and subsequently Yes-associated protein (YAP). YAP inactivation relieved the inhibition of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog G (MAFG), allowing MAFG to transactivate the stemness genes , , and . Inactivation also restored β8 expression, thereby forming a closed mechanical loop. Importantly, MAFG expression is correlated with worse prognosis. Our findings provide mechanical insights into the regulation of tumor cell dedifferentiation, which has therapeutic implications for exploring innovative strategies to attack malignancies.
PubMed: 37614365
DOI: 10.34133/research.0215 -
Molecular Psychiatry Nov 2023Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome... (Review)
Review
Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome side-effects, and unclear mechanisms of action. Advances in drug development for the treatment of bipolar disorder remain incremental and have come largely from repurposing drugs used for other psychiatric conditions, a strategy that has failed to find truly revolutionary therapies, as it does not target the mood instability that characterises the condition. The lack of therapeutic innovation in the bipolar disorder field is largely due to a poor understanding of the underlying disease mechanisms and the consequent absence of validated drug targets. A compelling new treatment target is the Ca-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme. CaMKK2 is highly enriched in brain neurons and regulates energy metabolism and neuronal processes that underpin higher order functions such as long-term memory, mood, and other affective functions. Loss-of-function polymorphisms and a rare missense mutation in human CAMKK2 are associated with bipolar disorder, and genetic deletion of Camkk2 in mice causes bipolar-like behaviours similar to those in patients. Furthermore, these behaviours are ameliorated by lithium, which increases CaMKK2 activity. In this review, we discuss multiple convergent lines of evidence that support targeting of CaMKK2 as a new treatment strategy for bipolar disorder.
Topics: Animals; Humans; Mice; Bipolar Disorder; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Mutation, Missense
PubMed: 37730845
DOI: 10.1038/s41380-023-02260-3 -
Pathogens (Basel, Switzerland) Nov 2023Host genetic factors significantly influence susceptibility to SARS-CoV-2 infection and COVID-19 severity. Among these genetic factors are single-nucleotide variants... (Review)
Review
Host genetic factors significantly influence susceptibility to SARS-CoV-2 infection and COVID-19 severity. Among these genetic factors are single-nucleotide variants (SNVs). and genes have been associated with severe COVID-19 in populations from the United Kingdom, Africa, and Latin America. IFNAR1 and IFNAR2 are subunits forming the type I interferon receptor (IFNAR). SNVs in the genes impact protein function, affecting antiviral response and disease phenotypes. This systematic review aimed to describe and variants associated with COVID-19 susceptibility and severity. Accordingly, the current review focused on and studies published between January 2021 and February 2023, utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol. The electronic search was conducted in PubMed databases using Boolean operators and inclusion and exclusion criteria. Of the 170 literature pieces, 11 studies were included. We include case reports of rare SNVs, defined by minor allele frequency (MAF) < 1%, and genome-wide associated studies (GWAS). Variants in and could potentially be new targets for therapies that limit the infection and the resulting inflammation by SARS-CoV-2 infection.
PubMed: 38003785
DOI: 10.3390/pathogens12111320 -
Scientific Reports Jul 2023Patients diagnosed with advanced cervical cancer (CC) have poor prognosis after primary treatment, and there is a lack of biomarkers for predicting patients with an... (Randomized Controlled Trial)
Randomized Controlled Trial
Patients diagnosed with advanced cervical cancer (CC) have poor prognosis after primary treatment, and there is a lack of biomarkers for predicting patients with an increased risk of recurrence of CC. Cuproptosis is reported to play a role in tumorigenesis and progression. However, the clinical impacts of cuproptosis-related lncRNAs (CRLs) in CC remain largely unclear. Our study attempted to identify new potential biomarkers to predict prognosis and response to immunotherapy with the aim of improving this situation. The transcriptome data, MAF files, and clinical information for CC cases were obtained from the cancer genome atlas, and Pearson correlation analysis was utilized to identify CRLs. In total, 304 eligible patients with CC were randomly assigned to training and test groups. LASSO regression and multivariate Cox regression were performed to construct a cervical cancer prognostic signature based on cuproptosis-related lncRNAs. Afterwards, we generated Kaplan-Meier curves, receiver operating characteristic curves and nomograms to verify the ability to predict prognosis of patients with CC. Genes for assessing differential expression among risk subgroups were also evaluated by functional enrichment analysis. Immune cell infiltration and the tumour mutation burden were analysed to explore the underlying mechanisms of the signature. Furthermore, the potential value of the prognostic signature to predict response to immunotherapy and sensitivity to chemotherapy drugs was examined. In our study, a risk signature containing eight cuproptosis-related lncRNAs (AL441992.1, SOX21-AS1, AC011468.3, AC012306.2, FZD4-DT, AP001922.5, RUSC1-AS1, AP001453.2) to predict the survival outcome of CC patients was developed, and the reliability of the risk signature was appraised. Cox regression analyses indicated that the comprehensive risk score is an independent prognostic factor. Moreover, significant differences were found in progression-free survival, immune cell infiltration, therapeutic response to immune checkpoint inhibitors, and IC50 for chemotherapeutic agents between risk subgroups, suggesting that our model can be well employed to assess the clinical efficacy of immunotherapy and chemotherapy. Based on our 8-CRLs risk signature, we were able to independently assess the outcome and response to immunotherapy of CC patients, and this signature might benefit clinical decision-making for individualized treatment.
Topics: Humans; Female; Uterine Cervical Neoplasms; RNA, Long Noncoding; Reproducibility of Results; Prognosis; Immunotherapy; Apoptosis; Copper; Frizzled Receptors
PubMed: 37400520
DOI: 10.1038/s41598-023-37898-0