Synergistic Signaling of TLR and IFNα/β Facilitates Escape of IL-18 Expression from Endotoxin Tolerance

Verweyen, Emely; Holzinger, Dirk; Weinhage, Toni; Hinze, Claas; Wittkowski, Helmut; Pickkers, Peter; Albeituni, Sabrin; Verbist, Katherine; Nichols, Kim E.; Schulert, Grant S.; Grom, Alexei A.; Foell, Dirk; Kessel, Christoph

doi:10.1164/rccm.201903-0659oc

Cited by 47 publications

(31 citation statements)

References 67 publications

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“…IL-18 is expressed by a wide range of tissues, including cells of the myeloid lineage but also epithelial cells, and (in contrast to IL-1) IL-18 messenger RNA (mRNA) expression and translation into its propeptide appear to be constitutive (33). However, beyond constitutive expression, a recent murine study (34) and human data from our laboratory (35) indicate that type I interferon (IFN) signaling plays a vital role in controlling IL-18 expression.…”

Section: Mechanismslinkingautoinflammationand Autoimmunity In Systemimentioning

confidence: 99%

“…Both cell types, in contrast to CD4+ T cells, express high levels of IL-18R (11,65,72). It has been demonstrated in both humans (35) and mice (34) that type I IFN signaling is associated with the production of IL-18. Thus, it can be speculated that tilting the IL-1/type I IFN balance toward increasing IFN signaling in response to IL-1 blockade (19,42) may benefit IL-18associated effects on innate and adaptive immune cells.…”

Section: Dampsandtherelevanceofsterileinflammationmentioning

confidence: 99%

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Innately Adaptive or Truly Autoimmune: Is There Something Unique About Systemic Juvenile Idiopathic Arthritis?

Kessel

Hedrich

Foell

2020

Arthritis & Rheumatology

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Systemic juvenile idiopathic arthritis (JIA) is a form of arthritis in childhood that is initially dominated by innate immunity-driven systemic inflammation and is thus considered a polygenic autoinflammatory disease. However, systemic JIA can progress toward an adaptive immunity-driven afebrile arthritis. Based on this observation of biphasic disease progression, a "window of opportunity" for optimal, individualized and target-directed treatment has been proposed. This hypothesis requires testing, and in this review we summarize current evidence regarding molecular factors that may contribute to the progression from an initially predominantly autoinflammatory disease phenotype to autoimmune arthritis. We consider the involvement of innately adaptive γδ T cells and natural killer T cells that express γδ or αβ T cell receptors but cannot be classified as either purely innate or adaptive cells, versus classic B and T lymphocytes in this continuum. Finally, we discuss our understanding of how and why some primarily autoinflammatory conditions can progress toward autoimmune-mediated disorders over the disease course while others do not and how this knowledge may be used to offer individualized treatment.Dr. Foell's work was supported by the DFG (project FO 354/11-1).

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Section: Mechanismslinkingautoinflammationand Autoimmunity In Systemimentioning

confidence: 99%

Section: Dampsandtherelevanceofsterileinflammationmentioning

confidence: 99%

Innately Adaptive or Truly Autoimmune: Is There Something Unique About Systemic Juvenile Idiopathic Arthritis?

Kessel

Hedrich

Foell

2020

Arthritis & Rheumatology

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“…The JAK/STAT3 pathway is aberrantly activated in various cancers, including OC, and is involved in functional regulation of the tumor microenvironment ( 44 ). Inflammatory factors could induce immune suppression and mediate immune escape ( 45 ). The P53 tumor suppressor pathway plays a key role in tumor immunology and the homeostatic regulation of immune responses ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Autophagy-Related Signatures Identified Two Distinct Subtypes for Evaluating the Tumor Immune Microenvironment and Predicting Prognosis in Ovarian Cancer

Chen

Lan

et al. 2021

Front. Oncol.

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Ovarian cancer (OC) is one of the most lethal gynecologic malignant tumors. The interaction between autophagy and the tumor immune microenvironment has clinical importance. Hence, it is necessary to explore reliable biomarkers associated with autophagy-related genes (ARGs) for risk stratification in OC. Here, we obtained ARGs from the MSigDB database and downloaded the expression profile of OC from TCGA database. The k-means unsupervised clustering method was used for clustering, and two subclasses of OC (cluster A and cluster B) were identified. SsGSEA method was used to quantify the levels of infiltration of 24 subtypes of immune cells. Metascape and GSEA were performed to reveal the differential gene enrichment in signaling pathways and cellular processes of the subtypes. We found that patients in cluster A were significantly associated with higher immune infiltration and immune-associated signaling pathways. Then, we established a risk model by LASSO Cox regression. ROC analysis and Kaplan-Meier analysis were applied for evaluating the efficiency of the risk signature, patients with low-risk got better outcomes than those with high-risk in overall survival. Finally, ULK2 and GABARAPL1 expression was further validated in clinical samples. In conclusion, Our study constructed an autophagy-related prognostic indicator, and identified two promising targets in OC.

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“…IL18 expression is largely constitutive in humans and in mice [108]. Il18 promoter includes a PU-box (a purine-rich sequence binding PU.1), NF-κB-recognition sequences, an ISRE site that was originally described to promote IRF-8-dependent induction of IL18 in macrophages [109] and GAS elements [110].…”

Section: Il-18 and Il-18bpmentioning

confidence: 99%

Transcriptional Regulation of Inflammasomes

Cornut¹,

Bourdonnay²,

Henry³

2020

Preprint

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Inflammasomes are multimolecular complexes with potent inflammatory activity. As such, their activity is tightly regulated at the transcriptional and post-transcriptional levels. In this review, we present the transcriptional regulation of inflammasome genes from sensors (e.g NLRP3) to substrates (e.g. IL-1β). Lineage-determining transcription factors shape inflammasome responses in different cell types with profound consequences on the responsiveness to inflammasome-activating stimuli. Pro-inflammatory signals (sterile or microbial) have a key transcriptional impact on inflammasome genes, which is largely mediated by NF-κB and, that translates into higher antimicrobial immune responses. Furthermore, diverse intrinsic (e.g. circadian clock, metabolites) or extrinsic (e.g. xenobiotics) signals are integrated by signal-dependent transcription factors and chromatin structure changes to modulate transcriptionally inflammasome responses. Finally, anti-inflammatory signals (e.g. IL-10) counterbalance inflammasome genes induction to limit deleterious inflammation. Transcriptional regulations thus appear as the first line of inflammasome regulation to raise the defense level in front of stress and infections but also to limit excessive or chronic inflammation.

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Synergistic Signaling of TLR and IFNα/β Facilitates Escape of IL-18 Expression from Endotoxin Tolerance

Cited by 47 publications

References 67 publications

Innately Adaptive or Truly Autoimmune: Is There Something Unique About Systemic Juvenile Idiopathic Arthritis?

Innately Adaptive or Truly Autoimmune: Is There Something Unique About Systemic Juvenile Idiopathic Arthritis?

Analysis of Autophagy-Related Signatures Identified Two Distinct Subtypes for Evaluating the Tumor Immune Microenvironment and Predicting Prognosis in Ovarian Cancer

Transcriptional Regulation of Inflammasomes

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