title: TDP-43 activates microglia through NF-κB and NLRP3 inflammasome.
abstract: Transactive response DNA-binding protein-43 (TDP-43) is a multifunctional nucleic acid binding protein present in ubiquitinated inclusions in tissues of patients with amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD). The ALS-associated mutations in the glycine-rich C-terminal domain of TDP-43 established a causal link between TDP-43 and disease, and conferred both loss- and gain-of-function properties in neurons. Since it has not been established whether these intra-neuronal changes are sufficient to cause ALS or whether non-cell autonomous neuronal-glial signaling could be involved, we investigated the extracellular effects of TDP-43 proteins on microglial activation and motoneuron toxicity. Wild-type, truncated 25kD C-terminal fragments, or mutant forms of TDP-43 all activated microglia and upregulated NOX2, TNF-α, and IL-1β, with WT forms being significantly less effective in activating microglia. This response to TDP-43 was mediated by its interaction with the microglial surface CD14 receptor and subsequent stimulation of the NF-κB and AP-1 pathways, as well as the intracellular inflammasome. At the cell surface, CD14 blocking antibodies suppressed microglial NF-κB activation and proinflammatory cytokine production mediated by TDP-43. Intracellularly, the NLRP3 inflammasome was induced and functional caspase-1 was produced augmenting the release of mature IL-1β. Further, TDP-43-mediated activation of microglia caused a proinflammatory cascade that was toxic to motoneurons. In the absence of microglia, TDP-43 was not toxic to motoneurons. The ability of TDP-43 to promote CD14-mediated activation of microglial NF-κB and AP-1 pathways, as well as the NLRP3 inflammasome, suggests the involvement of a non-cell autonomous proinflammatory signaling that enhances motoneuron injury, and may offer novel therapeutic targets in ALS.
authors.affiliation: Peggy and Gary Edwards ALS Laboratory, Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA.
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Peggy and Gary Edwards ALS Laboratory, Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Beers
authors.affiliation: Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Shaughn
authors.initials: S
authors.lastname: Bell
authors.affiliation: Peggy and Gary Edwards ALS Laboratory, Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA.
authors.forename: Jinghong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Peggy and Gary Edwards ALS Laboratory, Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA.
authors.forename: Shixiang
authors.initials: S
authors.lastname: Wen
authors.affiliation: Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Baloh
authors.affiliation: Peggy and Gary Edwards ALS Laboratory, Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA. Electronic address: sappel@houstonmethodist.org.
authors.forename: Stanley H
authors.initials: SH
authors.lastname: Appel
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D004622:Embryo, Mammalian; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012333:RNA, Messenger / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology; D014162:Transfection
chemical_list: D000906:Antibodies; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D053583:Interleukin-1beta; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D012333:RNA, Messenger; D012176:Retinoids; C106195:SR 11302; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D020170:Caspase 1
keywords: CD14; Microglia; NF-κB; NLRP3 inflammasome; TDP-43