TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy

Sharma, Deepika; Malik, Ankit; Guy, Clifford S.; Vogel, Peter; Kanneganti, Thirumala‐Devi

doi:10.1172/jci121372

Cited by 40 publications

(30 citation statements)

References 88 publications

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“…In a mouse model of FMF, TNF signaling through TNF receptor 1 (TNFR1) was critical for driving pathogenic overexpression of Mefv, supporting earlier studies. 36,37 Other putative transcription factor-binding sites have been identified but are poorly studied, including those for SPI-1, AP-1 (c-Jun/c-Fos), and Runt family transcription factors. 34 Patients with mutations associated with FMF display varying severity of disease, and mutations in the promoter region (c.−614C>G or c.−382C>T) are associated with decreased or increased MEFV expression, respectively, suggesting that differential gene expression may play a clinically important role in FMF.…”

Section: Upstream Regulatory Moleculesmentioning

confidence: 99%

Toward targeting inflammasomes: insights into their regulation and activation

2020

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Inflammasomes are multi-component signaling complexes critical to the initiation of pyroptotic cell death in response to invading pathogens and cellular damage. A number of innate immune receptors have been reported to serve as inflammasome sensors. Activation of these sensors leads to the proteolytic activation of caspase-1, a proinflammatory caspase responsible for the cleavage of proinflammatory cytokines interleukin-1β and interleukin-18 and the effector of pyroptotic cell death, gasdermin D. Though crucial to the innate immune response to infection, dysregulation of inflammasome activation can lead to the development of inflammatory diseases, neurodegeneration, and cancer. Therefore, clinical interest in the modulation of inflammasome activation is swiftly growing. As such, it is imperative to develop a mechanistic understanding of the regulation of these complexes. In this review, we divide the regulation of inflammasome activation into three parts. We discuss the transcriptional regulation of inflammasome components and related proteins, the post-translational mechanisms of inflammasome activation, and advances in the understanding of the structural basis of inflammasome activation.

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Section: Upstream Regulatory Moleculesmentioning

confidence: 99%

Toward targeting inflammasomes: insights into their regulation and activation

2020

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“…Its association with apoptosis-associated speck-like protein (ASC) leads to activation of a multiprotein inflammasome complex and downstream production of the potent pro-inflammatory and pyrogenic cytokine interleukin-1β (IL-1β) by neutrophils, monocytes, dendritic cells, and synovial fibroblasts. Recent data suggest a key role for the pro-inflammatory cytokine tumour necrosis factor-α (TNF-α) in modulation of pyrin expression and inflammasome activation [7]. However, pyrin also facilitates autophagic degradation of other inflammasome components, underscoring the complexity of this protein's function.…”

Section: Introductionmentioning

confidence: 99%

Periodic fever syndromes: beyond the single gene paradigm

et al. 2019

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Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease in Canada and is characterized by a clinical syndrome of episodic inflammatory symptoms. Traditionally, the disease is defined by autosomal recessive inheritance of MEFV gene variants, yet FMF also not uncommonly manifests in individuals with only one identified disease-associated allele. Increasing availability and affordability of gene sequencing has led to the identification of multiple MEFV variants; however, they are often of unknown clinical significance. Variants in other genes affecting overlapping or distinct inflammatory signaling pathwaystogether with gene-environment interactions including epigenetic modulationlikely underlie the significant genetic and phenotypic heterogeneity seen among patients with this disease. We review recent evidence of the expanding spectrum of FMF genotype and phenotype and suggest that current drug funding schemes restricting biologic agents to patients with homozygous mutations have not kept pace with our biological understanding of the disease.

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“…TNFα‐induced expression of MEFV is dependent on binding of two transcription factors, NF‐kB p65 and C/EBPβ, to the promoter 25 . Studies using mouse bone marrow‐derived macrophages (BMDMs) indicate that TNFα signaling is important for TLR ligands such as LPS to upregulate production of pyrin 26 . Additionally, TNFα signaling is important for autoinflammatory disease phenotypes in mice with knocked‐in B30.2 domain variants 26 (see below).…”

Section: Mefv Expressionmentioning

confidence: 99%

The pyrin inflammasome and the Yersinia effector interaction

Malik

Bliska

2020

Immunological Reviews

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Pyrin is a cytosolic pattern‐recognition receptor that normally functions as a guard to trigger capase‐1 inflammasome assembly in response to bacterial toxins and effectors that inactivate RhoA. The MEFV gene encoding human pyrin is preferentially expressed in phagocytes. Key domains in pyrin include a pyrin domain (PYD), a linker region, and a B30.2 domain. Binding of ASC to pyrin by a PYD‐PYD interaction triggers inflammasome assembly. Pyrin is held in an inactive conformation by negative regulation mechanisms to avoid premature inflammasome assembly. One mechanism of negative regulation involves phosphorylation of the linker by PRK kinase which in turn is positively regulated by active RhoA. The B30.2 domain also negatively regulates pyrin. Gain of function mutations in MEFV responsible for the autoinflammatory disease Familial Mediterranean Fever (FMF) map to exon 10 encoding the B30.2 domain. Insights into pyrin regulation have come from studies of several Yersinia effectors, which are injected into phagocytes and interact with the RhoA‐PRK‐pyrin axis during infection. Two effectors, YopE and YopT, inactivate RhoA to disrupt phagocytic signaling. To counteract an effector‐triggered immune response, a third effector, YopM, binds to and inhibits pyrin by hijacking PRK and RSK and directing linker phosphorylation. Inhibition of pyrin by YopM is required for virulence of Yersinia pestis, the agent of plague. Recent results from infection studies with human phagocytes and mice producing pyrin B30.2 FMF variants show that gain of function MEFV mutations bypass inhibition by YopM. Population genetic data suggest that MEFV mutations were selected for in individuals of Mediterranean decent during historic plague pandemics. This review discusses current concepts of pyrin regulation and its interaction with Yersinia effectors.

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TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy

Cited by 40 publications

References 88 publications

Toward targeting inflammasomes: insights into their regulation and activation

Toward targeting inflammasomes: insights into their regulation and activation

Periodic fever syndromes: beyond the single gene paradigm

The pyrin inflammasome and the Yersinia effector interaction

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