The thioredoxin‐1 inhibitor Txnip restrains effector T‐cell and germinal center B‐cell expansion

Muri, Jonathan; Thut, Helen; Köpf, Manfred

doi:10.1002/eji.202048851

Cited by 38 publications

(31 citation statements)

References 29 publications

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“…We thus examined the 50 transcripts most correlated with ZFP36L2 in Trms/Th17/Tc17 cells (ρ > 0.4, <0.2% of assessed transcripts, p < 6.1 × 10 −364 , excluding ribosomal or mitochondrial transcripts; Table S5 ) for prior biological evidence of immune pathway restriction. Strikingly, many inflammation-suppressing genes that we noted earlier as downregulated in psoriatic T cells were found in this set, including ZFP36 , SOCS1 , SOCS3 , CCL22 , and CD69 , as well as the global quiescence enforcers BTG1 39 and TXNIP 40 ( Figure 4 A). We thus termed these genes, which appear coherently suppressed in the highest cytokine-expressing single Th17/Tc17 cells, the ZFP36L2 inflammation-suppressive transcriptional program, or ZIST .…”

Section: Resultsmentioning

confidence: 58%

A single-cell transcriptional gradient in human cutaneous memory T cells restricts Th17/Tc17 identity

Cook

Taylor

Liu

et al. 2022

Cell Reports Medicine

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Section: Resultsmentioning

confidence: 58%

A single-cell transcriptional gradient in human cutaneous memory T cells restricts Th17/Tc17 identity

Cook

Taylor

Liu

et al. 2022

Cell Reports Medicine

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“…The increased expression of these genes is therefore in line with a deregulation of CD4+ T cells in active CeD. In the pre-diagnostic marker category, the top genes were associated to diverse functions, such as thioredoxin interacting protein TXNIP (a regulator of cellular redox state whose function in CD4+ T cells seems to affect the proliferation of effector T cells) ( 34 ), and IL32 (previously associated with the progression of various inflammatory disorders including inflammatory bowel disease and gastric inflammation) ( 35 , 36 ).…”

Section: Resultsmentioning

confidence: 91%

Single-Cell RNA Sequencing of Peripheral Blood Mononuclear Cells From Pediatric Coeliac Disease Patients Suggests Potential Pre-Seroconversion Markers

et al. 2022

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Celiac Disease (CeD) is a complex immune disorder involving villous atrophy in the small intestine that is triggered by gluten intake. Current CeD diagnosis is based on late-stage pathophysiological parameters such as detection of specific antibodies in blood and histochemical detection of villus atrophy and lymphocyte infiltration in intestinal biopsies. To date, no early onset biomarkers are available that would help prevent widespread villous atrophy and severe symptoms and co-morbidities. To search for novel CeD biomarkers, we used single-cell RNA sequencing (scRNAseq) to investigate PBMC samples from 11 children before and after seroconversion for CeD and 10 control individuals matched for age, sex and HLA-genotype. We generated scRNAseq profiles of 9559 cells and identified the expected major cellular lineages. Cell proportions remained stable across the different timepoints and health conditions, but we observed differences in gene expression profiles in specific cell types when comparing patient samples before and after disease development and comparing patients with controls. Based on the time when transcripts were differentially expressed, we could classify the deregulated genes as biomarkers for active CeD or as potential pre-diagnostic markers. Pathway analysis showed that active CeD biomarkers display a transcriptional profile associated with antigen activation in CD4+ T cells, whereas NK cells express a subset of biomarker genes even before CeD diagnosis. Intersection of biomarker genes with CeD-associated genetic risk loci pinpointed genetic factors that might play a role in CeD onset. Investigation of potential cellular interaction pathways of PBMC cell subpopulations highlighted the importance of TNF pathways in CeD. Altogether, our results pinpoint genes and pathways that are altered prior to and during CeD onset, thereby identifying novel potential biomarkers for CeD diagnosis in blood.

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“…Previous studies have shown that biological stimuli induced cells to produce a large amount of ROS, and the increased levels of ROS disrupted the intracellular TRX–TXNIP balance [ 62 ]. TXNIP was a pivotal endogenous negative regulator of cellular redox balance [ 22 , 63 , 64 ] that was highly expressed in immune cells and played a role in regulating lymphocyte cycle progression and proliferation in the immune system [ 62 , 65 ]. Sheng-Min Hsu, et al have confirmed suppression of the ROS could alleviate EAU [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Melatonin, an endogenous hormone, modulates Th17 cells via the reactive-oxygen species/TXNIP/HIF-1α axis to alleviate autoimmune uveitis

Huang

et al. 2022

J Neuroinflammation

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Background Melatonin, an indoleamine produced by the pineal gland, plays a pivotal role in maintaining circadian rhythm homeostasis. Recently, the strong antioxidant and anti-inflammatory properties of melatonin have attracted attention of researchers. We evaluated the therapeutic efficacy of melatonin in experimental autoimmune uveitis (EAU), which is a representative animal model of human autoimmune uveitis. Methods EAU was induced in mice via immunization with the peptide interphotoreceptor retinoid binding protein 1–20 (IRBP1–20). Melatonin was then administered via intraperitoneal injection to induce protection against EAU. With EAU induction for 14 days, clinical and histopathological scores were graded to evaluate the disease progression. T lymphocytes accumulation and the expression of inflammatory cytokines in the retinas were assessed via flow cytometry and RT-PCR, respectively. T helper 1 (Th1), T helper 17 (Th17), and regulatory T (Treg) cells were detected via flow cytometry for both in vivo and in vitro experiments. Reactive-oxygen species (ROS) from CD4 + T cells was tested via flow cytometry. The expression of thioredoxin-interacting protein (TXNIP) and hypoxia-inducible factor 1 alpha (HIF-1α) proteins were quantified via western blot. Results Melatonin treatment resulted in notable attenuation of ocular inflammation in EAU mice, evidenced by decreasing optic disc edema, few signs of retinal vasculitis, and minimal retinal and choroidal infiltrates. Mechanistic studies revealed that melatonin restricted the proliferation of peripheral Th1 and Th17 cells by suppressing their transcription factors and potentiated Treg cells. In vitro studies corroborated that melatonin restrained the polarization of retina-specific T cells towards Th17 and Th1 cells in addition to enhancing the proportion of Treg cells. Pretreatment of retina-specific T cells with melatonin failed to induce EAU in naïve recipients. Furthermore, the ROS/ TXNIP/ HIF-1α pathway was shown to mediate the therapeutic effect of melatonin in EAU. Conclusions Melatonin regulates autoimmune T cells by restraining effector T cells and facilitating Treg generation, indicating that melatonin could be a hopeful treatment alternative for autoimmune uveitis.

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The thioredoxin‐1 inhibitor Txnip restrains effector T‐cell and germinal center B‐cell expansion

Cited by 38 publications

References 29 publications

A single-cell transcriptional gradient in human cutaneous memory T cells restricts Th17/Tc17 identity

A single-cell transcriptional gradient in human cutaneous memory T cells restricts Th17/Tc17 identity

Single-Cell RNA Sequencing of Peripheral Blood Mononuclear Cells From Pediatric Coeliac Disease Patients Suggests Potential Pre-Seroconversion Markers

Melatonin, an endogenous hormone, modulates Th17 cells via the reactive-oxygen species/TXNIP/HIF-1α axis to alleviate autoimmune uveitis

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