TDP-43 activates microglia through NF-κB and NLRP3 inflammasome

• Published in: Experimental neurology Vol. 273; pp. 24 - 35
• Main Authors: Zhao, Weihua, Beers, David R., Bell, Shaughn, Wang, Jinghong, Wen, Shixiang, Baloh, Robert H., Appel, Stanley H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2015
• Subjects: Animals; Animals, Newborn; Antibodies - pharmacology; Carrier Proteins - metabolism; Caspase 1 - metabolism; CD14; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - pharmacology; Embryo, Mammalian; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Lipopolysaccharide Receptors - immunology; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Microglia; Microglia - metabolism; Motor Neurons - drug effects; Motor Neurons - metabolism; Mutation - genetics; NADPH Oxidase 2; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; NF-kappa B - metabolism; NF-κB; NLR Family, Pyrin Domain-Containing 3 Protein; NLRP3 inflammasome; Retinoids - pharmacology; RNA, Messenger - metabolism; Spinal Cord - cytology; TDP-43; Transfection; NF-κB; CD14; NLRP3 inflammasome; TDP-43; Microglia
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2015.07.019

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.
•TDP-43 is able to cause cytotoxic microglial activation.•TDP-43 binds to CD14 receptor, and triggers pro-inflammatory signaling pathways.•Microglia activated by TDP-43 are toxic to motoneurons.