Absent in Melanoma 2 proteins in SLE

Choubey, Divaker; Panchanathan, Ravichandran

doi:10.1016/j.clim.2016.12.011

Cited by 37 publications

(39 citation statements)

References 109 publications

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“…This may reflect increased levels of circulating BAFF in SLE patients, which is known to repress Aim2 expression(45). The role of Aim2 in SLE is multifaceted and may have inhibitory and promoting effects on autoimmunity (reviewed in (46)). No correlation of another inflammasome scaffold, NLRP1, with IFN scores was noted.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Inflammasome Activity in Systemic Lupus Erythematosus Is Mediated via Type I Interferon–Induced Up‐Regulation of Interferon Regulatory Factor 1

Liu

Berthier

Kahlenberg

2017

Arthritis & Rheumatology

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Objective The inflammasome complex is a driver of organ damage in systemic lupus erythematosus (SLE). While type I interferons (IFNs) are well established as mediators of SLE pathogenesis, their role in inflammasome activation in SLE has not been assessed. Thus, we examined type I IFNs as regulators of the inflammasome and identified interferon regulatory factor 1 (IRF1) as critical for inflammasome hyperactivity in SLE. Methods SLE patients fulfilled ≥4 ACR criteria and were recruited from the University of Michigan Lupus Cohort. Primary monocytes were isolated from SLE patients or healthy controls by negative selection, treated with inflammasome activators in the presence or absence of IFNα, and IL-1β secretion was measured by ELISA. Expression levels of interferon and inflammasome-related molecules were assessed by real-time PCR and Western blotting. IRF1 expression was specifically downregulated by siRNA transfection and a chemical inhibitor. Results SLE monocytes exhibited increased expression and enhanced activation of the inflammasome by ATP when compared to control monocytes. Expression of inflammasome and interferon-regulated genes was significantly correlated in lupus, but not control, monocytes. Inflammasome activity was increased after prolonged exposure to IFNα. Reduction of IRF1 expression via siRNA blocked caspase-1 upregulation after treatment with IFNα. Importantly, hyperactivity of the inflammasome in lupus monocytes was significantly reduced after knock-down or inhibition of IRF1. Conclusion Prolonged type I IFN exposure, as seen in SLE patients, primes monocytes for robust inflammasome activation in an IRF1-dependent manner. IRF1 inhibition may serve as a novel target for treatment of SLE-associated inflammation and organ damage.

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Section: Discussionmentioning

confidence: 99%

Enhanced Inflammasome Activity in Systemic Lupus Erythematosus Is Mediated via Type I Interferon–Induced Up‐Regulation of Interferon Regulatory Factor 1

Liu

Berthier

Kahlenberg

2017

Arthritis & Rheumatology

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“…In addition to its role in triggering inflammation, self‐DNA is also associated with typical autoimmune diseases. ALRs and AIM2 have been implicated in systemic lupus erythematous (SLE) . SLE is a chronic autoimmune disease that can affect most organs.…”

Section: Aim2 In Health and Diseasementioning

confidence: 99%

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

Lugrin

Martinon

2017

Immunological Reviews

256

182

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Recognition of pathogens and altered self must be efficient and highly specific to orchestrate appropriate responses while limiting excessive inflammation and autoimmune reaction to normal self. AIM2 is a member of innate immune sensors that detects the presence of DNA, arguably the most conserved molecules in living organisms. However, AIM2 achieves specificity by detecting altered or mislocalized DNA molecules. It can detect damaged DNA, and the aberrant presence of DNA within the cytosolic compartment such as genomic DNA released into the cytosol upon loss of nuclear envelope integrity. AIM2 is also a key sensor of pathogens that detects the presence of foreign DNA accumulating in the cytosol during the life cycle of intracellular pathogens including viruses, bacteria, and parasites. AIM2 activation initiates the assembly of the inflammasome, an innate immune complex that leads to the activation of inflammatory caspases. This triggers the maturation and secretion of the cytokines IL-1β and IL-18. It can also initiate pyroptosis, a proinflammatory form of cell death. The AIM2 inflammasome contributes to physiological responses and diseases. It is a key player in host defenses, but its deregulation can contribute immune-linked diseases, such as autoinflammatory and autoimmune pathologies. Moreover, AIM2 may play a role in cancer development. Recent studies have shown that the detection of self-DNA species by AIM2 is an important factor that contributes to diseases associated with perturbation of cellular homeostasis. Thus, in addition of being a sensor of pathogen associated molecular patterns (PAMPs), the AIM2 inflammasome is emerging as a key guardian of cellular integrity.

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“…In line with this, the activity of AIM2 inflammasome is very low in macrophages of NZB mice [28]. p202 might contribute to SLE development through regulation of AIM2 inflammasome [32,34,35]. p202 is also implicated in the progression of other autoimmune diseases such as glomerulonephritis [36].…”

Section: Introductionmentioning

confidence: 66%

“…SLE is an interferonopathy in which type I IFNs are highly induced and hyperactive . To determine whether IFI16‐β might also be induced in SLE patients, RT–qPCR was performed with peripheral blood mononuclear cells (PBMCs) isolated from SLE patients and healthy subjects.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of AIM 2 inflammasome activation by a novel transcript isoform of IFI 16

Wang

Deng

et al. 2018

EMBO Reports

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Mouse p202 is a disease locus for lupus and a dominant-negative inhibitor of AIM2 inflammasome activation. A human homolog of p202 has not been identified so far. Here, we report a novel transcript isoform of human IFI16-designated IFI16-β, which has a domain architecture similar to that of mouse p202. Like p202, IFI16-β contains two HIN domains, but lacks the pyrin domain. IFI16-β is ubiquitously expressed in various human tissues and cells. Its mRNA levels are also elevated in leukocytes of patients with lupus, virus-infected cells, and cells treated with interferon-β or phorbol ester. IFI16-β co-localizes with AIM2 in the cytoplasm, whereas IFI16-α is predominantly found in the nucleus. IFI16-β interacts with AIM2 to impede the formation of a functional AIM2-ASC complex. In addition, IFI16-β sequesters cytoplasmic dsDNA and renders it unavailable for AIM2 sensing. Enforced expression of IFI16-β inhibits the activation of AIM2 inflammasome, whereas knockdown of IFI16-β augments interleukin-1β secretion triggered by dsDNA but not dsRNA Thus, cytoplasm-localized IFI16-β is functionally equivalent to mouse p202 that exerts an inhibitory effect on AIM2 inflammasome.

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Absent in Melanoma 2 proteins in SLE

Cited by 37 publications

References 109 publications

Enhanced Inflammasome Activity in Systemic Lupus Erythematosus Is Mediated via Type I Interferon–Induced Up‐Regulation of Interferon Regulatory Factor 1

Enhanced Inflammasome Activity in Systemic Lupus Erythematosus Is Mediated via Type I Interferon–Induced Up‐Regulation of Interferon Regulatory Factor 1

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

Inhibition of AIM 2 inflammasome activation by a novel transcript isoform of IFI 16

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