α1-antitrypsin mitigates NLRP3-inflammasome activation in amyloid β1–42-stimulated murine astrocytes
Abstract Background Neuroinflammation has an essential impact on the pathogenesis and progression of Alzheimer’s disease (AD). Mostly mediated by microglia and astrocytes, inflammatory processes lead to degeneration of neuronal cells. The NLRP3-inflammasome (NOD-like receptor family, pyrin domain co...
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doaj-d19d4b4fd72749d4a06e9595c819751b2020-11-24T21:27:06ZengBMCJournal of Neuroinflammation1742-20942018-09-0115111510.1186/s12974-018-1319-xα1-antitrypsin mitigates NLRP3-inflammasome activation in amyloid β1–42-stimulated murine astrocytesTaraneh Ebrahimi0Marcus Rust1Sarah Nele Kaiser2Alexander Slowik3Cordian Beyer4Andreas Rembert Koczulla5Jörg B. Schulz6Pardes Habib7Jan Philipp Bach8Department of Neurology, RWTH Aachen UniversityDepartment of Neurology, RWTH Aachen UniversityDepartment of Neurology, RWTH Aachen UniversityInstitute of Neuroanatomy, RWTH Aachen UniversityInstitute of Neuroanatomy, RWTH Aachen UniversityDepartment of Internal Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and MarburgDepartment of Neurology, RWTH Aachen UniversityDepartment of Neurology, RWTH Aachen UniversityDepartment of Neurology, RWTH Aachen UniversityAbstract Background Neuroinflammation has an essential impact on the pathogenesis and progression of Alzheimer’s disease (AD). Mostly mediated by microglia and astrocytes, inflammatory processes lead to degeneration of neuronal cells. The NLRP3-inflammasome (NOD-like receptor family, pyrin domain containing 3) is a key component of the innate immune system and its activation results in secretion of the proinflammatory effectors interleukin-1β (IL-1β) and interleukin-18 (IL-18). Under physiological conditions, cytosolic NLRP3-inflammsome is maintained in an inactive form, not able to oligomerize. Amyloid β1–42 (Aβ1–42) triggers activation of NLRP3-inflammasome in microglia and astrocytes, inducing oligomerization and thus recruitment of proinflammatory proteases. NLRP3-inflammasome was found highly expressed in human brains diagnosed with AD. Moreover, NLRP3-deficient mice carrying mutations associated with familial AD were partially protected from deficits associated with AD. The endogenous protease inhibitor α1-antitrypsin (A1AT) is known for its anti-inflammatory and anti-apoptotic properties and thus could serve as therapeutic agent for NLRP3-inhibition. A1AT protects neurons from glutamate-induced toxicity and reduces Aβ1–42-induced inflammation in microglial cells. In this study, we investigated the effect of Aβ1–42-induced NLRP3-inflammasome upregulation in primary murine astrocytes and its regulation by A1AT. Methods Primary cortical astrocytes from BALB/c mice were stimulated with Aβ1–42 and treated with A1AT. Regulation of NLRP3-inflammasome was examined by immunocytochemistry, PCR, western blot and ELISA. Our studies included an inhibitor of NLRP3 to elucidate direct interactions between A1AT and NLRP3-inflammasome components. Results Our study revealed that A1AT reduces Aβ1–42-dependent upregulation of NLRP3 at the mRNA and protein levels. Furthermore, A1AT time-dependently mitigated the expression of caspase 1 and its cleavage product IL-1β in Aβ1–42-stimulated astrocytes. Conclusion We conclude that Aβ1–42-stimulation results in an upregulation of NLRP3, caspase 1, and its cleavage products in astrocytes. A1AT time-dependently hampers neuroinflammation by downregulation of Aβ1–42-mediated NLRP3-inflammasome expression and thus may serve as a pharmaceutical opportunity for the treatment of Alzheimer’s disease.http://link.springer.com/article/10.1186/s12974-018-1319-xNeuroinflammationNLRP3NALP3InflammasomeAlzheimer’s diseaseAmyloid β |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Taraneh Ebrahimi Marcus Rust Sarah Nele Kaiser Alexander Slowik Cordian Beyer Andreas Rembert Koczulla Jörg B. Schulz Pardes Habib Jan Philipp Bach |
spellingShingle |
Taraneh Ebrahimi Marcus Rust Sarah Nele Kaiser Alexander Slowik Cordian Beyer Andreas Rembert Koczulla Jörg B. Schulz Pardes Habib Jan Philipp Bach α1-antitrypsin mitigates NLRP3-inflammasome activation in amyloid β1–42-stimulated murine astrocytes Journal of Neuroinflammation Neuroinflammation NLRP3 NALP3 Inflammasome Alzheimer’s disease Amyloid β |
author_facet |
Taraneh Ebrahimi Marcus Rust Sarah Nele Kaiser Alexander Slowik Cordian Beyer Andreas Rembert Koczulla Jörg B. Schulz Pardes Habib Jan Philipp Bach |
author_sort |
Taraneh Ebrahimi |
title |
α1-antitrypsin mitigates NLRP3-inflammasome activation in amyloid β1–42-stimulated murine astrocytes |
title_short |
α1-antitrypsin mitigates NLRP3-inflammasome activation in amyloid β1–42-stimulated murine astrocytes |
title_full |
α1-antitrypsin mitigates NLRP3-inflammasome activation in amyloid β1–42-stimulated murine astrocytes |
title_fullStr |
α1-antitrypsin mitigates NLRP3-inflammasome activation in amyloid β1–42-stimulated murine astrocytes |
title_full_unstemmed |
α1-antitrypsin mitigates NLRP3-inflammasome activation in amyloid β1–42-stimulated murine astrocytes |
title_sort |
α1-antitrypsin mitigates nlrp3-inflammasome activation in amyloid β1–42-stimulated murine astrocytes |
publisher |
BMC |
series |
Journal of Neuroinflammation |
issn |
1742-2094 |
publishDate |
2018-09-01 |
description |
Abstract Background Neuroinflammation has an essential impact on the pathogenesis and progression of Alzheimer’s disease (AD). Mostly mediated by microglia and astrocytes, inflammatory processes lead to degeneration of neuronal cells. The NLRP3-inflammasome (NOD-like receptor family, pyrin domain containing 3) is a key component of the innate immune system and its activation results in secretion of the proinflammatory effectors interleukin-1β (IL-1β) and interleukin-18 (IL-18). Under physiological conditions, cytosolic NLRP3-inflammsome is maintained in an inactive form, not able to oligomerize. Amyloid β1–42 (Aβ1–42) triggers activation of NLRP3-inflammasome in microglia and astrocytes, inducing oligomerization and thus recruitment of proinflammatory proteases. NLRP3-inflammasome was found highly expressed in human brains diagnosed with AD. Moreover, NLRP3-deficient mice carrying mutations associated with familial AD were partially protected from deficits associated with AD. The endogenous protease inhibitor α1-antitrypsin (A1AT) is known for its anti-inflammatory and anti-apoptotic properties and thus could serve as therapeutic agent for NLRP3-inhibition. A1AT protects neurons from glutamate-induced toxicity and reduces Aβ1–42-induced inflammation in microglial cells. In this study, we investigated the effect of Aβ1–42-induced NLRP3-inflammasome upregulation in primary murine astrocytes and its regulation by A1AT. Methods Primary cortical astrocytes from BALB/c mice were stimulated with Aβ1–42 and treated with A1AT. Regulation of NLRP3-inflammasome was examined by immunocytochemistry, PCR, western blot and ELISA. Our studies included an inhibitor of NLRP3 to elucidate direct interactions between A1AT and NLRP3-inflammasome components. Results Our study revealed that A1AT reduces Aβ1–42-dependent upregulation of NLRP3 at the mRNA and protein levels. Furthermore, A1AT time-dependently mitigated the expression of caspase 1 and its cleavage product IL-1β in Aβ1–42-stimulated astrocytes. Conclusion We conclude that Aβ1–42-stimulation results in an upregulation of NLRP3, caspase 1, and its cleavage products in astrocytes. A1AT time-dependently hampers neuroinflammation by downregulation of Aβ1–42-mediated NLRP3-inflammasome expression and thus may serve as a pharmaceutical opportunity for the treatment of Alzheimer’s disease. |
topic |
Neuroinflammation NLRP3 NALP3 Inflammasome Alzheimer’s disease Amyloid β |
url |
http://link.springer.com/article/10.1186/s12974-018-1319-x |
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