RIG-I contributes to the innate immune response after cerebral ischemia

Brand, Frank; Vaccari, Juan Carlos de Rivero; Mejias, Nancy H.; Alonso, Ofelia F.; Vaccari, Juan Pablo de Rivero

doi:10.1186/s12950-015-0101-4

Cited by 16 publications

(15 citation statements)

References 29 publications

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“…Our results show that the overexpression of RIG-I triggers IRF3 phosphorylation and IFN-β transcription per se . Interestingly, it has been reported that RIG-I is also overexpressed in the hippocampus after focal cerebral hypoxia 25 .…”

Section: Discussionmentioning

confidence: 99%

Hypoxia triggers IFN-I production in muscle: Implications in dermatomyositis

Luna

Suárez‐Calvet

Lleixà

et al. 2017

Sci Rep

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Dermatomyositis is an inflammatory myopathy characterized by symmetrical proximal muscle weakness and skin changes. Muscle biopsy hallmarks include perifascicular atrophy, loss of intramuscular capillaries, perivascular and perimysial inflammation and the overexpression of IFN-inducible genes. Among them, the retinoic-acid inducible gene 1 (RIG-I) is specifically overexpressed in perifascicular areas of dermatomyositis muscle. The aim of this work was to study if RIG-I expression may be modulated by hypoxia using an in vitro approach. We identified putative hypoxia response elements (HRE) in RIG-I regulatory regions and luciferase assays confirmed that RIG-I is a new HIF-inducible gene. We observed an increase expression of RIG-I both by Real time PCR and Western blot in hypoxic conditions in human muscle cells. Cell transfection with a constitutive RIG-I expression vector increased levels of phospho-IRF-3, indicating that RIG-I promotes binding of transcription factors to the enhancer sequence of IFN. Moreover, release of IFN-β was observed in hypoxic conditions. Finally, HIF-1α overexpression was confirmed in the muscle biopsies and in some RIG-I positive perifascicular muscle fibres but not in controls. Our results indicate that hypoxia triggers the production of IFN-I in vitro, and may contribute to the pathogenesis of DM together with other inflammatory factors.

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Section: Discussionmentioning

confidence: 99%

Hypoxia triggers IFN-I production in muscle: Implications in dermatomyositis

Luna

Suárez‐Calvet

Lleixà

et al. 2017

Sci Rep

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“…For immunoblot analysis of NLRP1 and ASC proteins from clots of nine different patients, protein was extracted and resolved as described in ( Brand et al, 2015 ). Briefly, equal amounts of protein lysates (20 μg of total protein) were resolved in 4–20% Criterion TGX Stain-Free precasted gels (Bio-Rad).…”

Section: Methodsmentioning

confidence: 99%

Netosis and Inflammasomes in Large Vessel Occlusion Thrombi

et al. 2021

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The inflammatory response appears to play a critical role in clotting in which neutrophil extracellular traps (NETs) are the major drivers of thrombosis in acute ischemic stroke (AIS). The inflammasome is an innate immune complex involved in the activation of interleukin (IL)-18 and IL-1β through caspase-1, but whether the inflammasome plays a role in NETosis in AIS remains poorly understood. Here we assessed the levels of inflammasome signaling proteins in NETs and their association with clinical and procedural outcomes of mechanical thrombectomy for AIS. Electron microscopy and immunofluorescence indicate the presence of NETs in thrombi of patients with AIS. Moreover, the inflammasome signaling proteins caspase-1 and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) were also present in clots associated with the marker of NETosis citrullinated histone 3H (CitH3). Analysis of protein levels by a simple plex assay show that caspase-1, ASC and interleukin (IL)-1β were significantly elevated in clots when compared to plasma of AIS patients and healthy controls, while IL-18 levels were lower. Moreover, multivariate analyses show that IL-1β levels in clots contribute to the number of passes to achieve complete recanalization, and that ASC, caspase-1 and IL-18 are significant contributors to time to recanalization. Thus, inflammasome proteins are elevated in NETs present in thrombi of patients with AIS that contribute to poor outcomes following stroke.

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“…Protein levels of inflammasome signaling proteins were determined in the cytosolic and mitochondrial fractions as described in [ 7 ]. Briefly, protein lysates were resolved in 10–20% Criterion TGX Stain-Free precasted gels (Bio-Rad), using antibodies (1:1000 dilution) to NLRC4 (Novus Biologicals, cat# NBP2–41124), caspase-1 (Novus Biologicals, cat# NB100–56565), caspase-11 (Novus Biologicals, cat# MAB8648), ASC (Santa Cruz, cat# sc-271054), IL-1β (Cell Signaling, cat# 12242S), IL-18 (Abcam, cat# ab71495), HSP60 (Cell Signaling, cat#12165) and β-actin (Sigma Aldric, cat# A5441).…”

Section: Methodsmentioning

confidence: 99%

Contribution of the inflammasome to inflammaging

et al. 2018

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BackgroundInflammation is a natural part of the aging process. This process is referred to as inflammaging. Inflammaging has been associated with deleterious outcomes in the aging brain in diseases such as Alzheimer’s disease and Parkinson’s disease. The inflammasome is a multi-protein complex of the innate immune response involved in the activation of caspase-1 and the processing of the inflammatory cytokines interleukin (IL)-1β and IL-18. We have previously shown that the inflammasome plays a role in the aging process in the brain. In this study, we analyzed the brain of young (3 months old) and aged (18 months old) mice for the expression of inflammasome proteins.ResultsOur findings indicate that the inflammasome proteins NLRC4, caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and IL-18 are elevated in the cytosol of cortical lysates in aged mice when compared to young. In addition, in the cytosolic fraction of hippocampal lysates in aged mice, we found an increase in NLRC4, caspase-1, caspase-11, ASC and IL-1β. Moreover, we found higher levels of ASC in the mitochondrial fraction of aged mice when compared to young, consistent with higher levels of the substrate of pyroptosis gasdermin-D (GSDM-D) and increased pyroptosome formation (ASC oligomerization). Importantly, in this study we obtained fibroblasts from a subject that donated his cells at three different ages (49, 52 and 64 years old (y/o)) and found that the protein levels of caspase-1 and ASC were higher at 64 than at 52 y/o. In addition, the 52 y/o cells were more susceptible to oxidative stress as determined by lactose dehydrogenase (LDH) release levels. However, this response was ameliorated by inhibition of the inflammasome with Ac-Tyr-Val-Ala-Asp-Chloromethylketone (Ac-YVAD-CMK). In addition, we found that the protein levels of ASC and IL-18 are elevated in the serum of subjects over the age of 45 y/o when compared to younger subjects, and that ASC was higher in Caucasians than Blacks and Hispanics, whereas IL-18 was higher in Caucasians than in blacks, regardless of age.ConclusionsTaken together, our data indicate that the inflammasome contributes to inflammaging and that the inflammasome-mediated cell death mechanism of pyroptosis contributes to cell demise in the aging brain.

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RIG-I contributes to the innate immune response after cerebral ischemia

Cited by 16 publications

References 29 publications

Hypoxia triggers IFN-I production in muscle: Implications in dermatomyositis

Hypoxia triggers IFN-I production in muscle: Implications in dermatomyositis

Netosis and Inflammasomes in Large Vessel Occlusion Thrombi

Contribution of the inflammasome to inflammaging

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