title: NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients.
abstract: Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of motoneurons in the cerebral cortex, brainstem and spinal cord. Neuroinflammation plays an important role in the pathogenesis of ALS and involves the activation of microglia and astrocytes. Intracellular inflammasome complexes are part of the innate immunity as they sense and execute host inflammatory responses. The best characterized component is the NLRP3 inflammasome comprised of the NLR protein NLRP3, the adaptor ASC and pro-caspase 1. The NLRP3 inflammasome is critical for the activation of caspase 1 and the processing and release of IL1β and IL18. In this study, we investigated the expression, activation and co-localization of the NLRP3 inflammasome in the spinal cord of male SOD1(G93A) mice carrying a mutant human superoxide dismutase 1 (SOD1) variant and regarded as an animal model for ALS as well as in post-mortem tissue of ALS patients. NLRP3 and its molecular components as well as IL1β were already detectable in SOD1 mice at a pre-symptomatic stage after 9 weeks and further increased in 14 week old animals. Spinal cord astrocytes were identified as the major cell type expressing NLRP3 components. In human ALS tissue, we also found increased NLRP3, ASC, IL18 and active caspase 1 levels compared to control patients. Our findings suggest that astroglial NLRP3 inflammasome complexes are critically involved in neuroinflammation in ALS.
authors.affiliation: Institute of Neuroanatomy, RWTH Aachen University, Wendlingweg 2, Aachen, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Johann
authors.affiliation: Institute of Neuroanatomy, RWTH Aachen University, Wendlingweg 2, Aachen, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Heitzer
authors.affiliation: Institute of Neuroanatomy, RWTH Aachen University, Wendlingweg 2, Aachen, Germany.
authors.forename: Mithila
authors.initials: M
authors.lastname: Kanagaratnam
authors.affiliation: Institute of Neuropathology, RWTH Aachen University, Pauwelsstr. 30, Aachen, Germany.
authors.forename: Anand
authors.initials: A
authors.lastname: Goswami
authors.affiliation: Institute of Neuropathology, RWTH Aachen University, Pauwelsstr. 30, Aachen, Germany.
authors.forename: Tania
authors.initials: T
authors.lastname: Rizo
authors.affiliation: Institute of Neuropathology, RWTH Aachen University, Pauwelsstr. 30, Aachen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.affiliation: Division of Neuropathology, Department of Pathology, Academic Medical Centre, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Troost
authors.affiliation: Institute of Neuroanatomy, RWTH Aachen University, Wendlingweg 2, Aachen, Germany.
authors.forename: Cordian
authors.initials: C
authors.lastname: Beyer
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012333:RNA, Messenger / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D002352:Carrier Proteins; C587672:IL1B protein, mouse; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D012333:RNA, Messenger; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D020170:Caspase 1
keywords: IL-1b; SOD1(G93A); amyotrophic lateral sclerosis; caspase 1; glia; neuroinflammation