1. Beclin1-driven autophagy modulates the inflammatory response of microglia via NLRP3.
- Author
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Houtman J, Freitag K, Gimber N, Schmoranzer J, Heppner FL, and Jendrach M
- Subjects
- Alzheimer Disease immunology, Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid beta-Protein Precursor physiology, Animals, Autophagosomes, Cytokines metabolism, Female, Inflammasomes, Inflammation metabolism, Inflammation pathology, Male, Mice, Mice, Knockout, Microglia metabolism, Microglia pathology, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Plaque, Amyloid metabolism, Plaque, Amyloid pathology, Presenilin-1 physiology, Autophagy, Beclin-1 physiology, Inflammation immunology, Microglia immunology, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Plaque, Amyloid immunology
- Abstract
Alzheimer's disease is characterized not only by extracellular amyloid plaques and neurofibrillary tangles, but also by microglia-mediated neuroinflammation. Recently, autophagy has been linked to the regulation of the inflammatory response. Thus, we investigated how an impairment of autophagy mediated by BECN1/Beclin1 reduction, as described in Alzheimer's disease patients, would influence cytokine production of microglia. Acutely stimulated microglia from Becn1 mice exhibited increased expression of IL-1beta and IL-18 compared to wild-type microglia.
+/- mice exhibited increased expression of IL-1beta and IL-18 compared to wild-type microglia. Becn1 microglia. Super-resolation microscopy revealed a very close association of NLRP3 aggregates and LC3-positive vesicles. Interestingly, CALCOCO2 colocalized with NLRP3 and its downregulation increased IL-1beta release. These data support the notion that selective autophagy can impact microglia activation by modulating IL-1beta and IL-18 production via NLRP3 degradation and thus present a mechanism how impaired autophagy could contribute to neuroinflammation in Alzheimer's disease.+/- APPPS1 mice also contained enhanced IL-1beta levels. The investigation of the IL-1beta/IL-18 processing pathway showed an elevated number of cells with inflammasomes and increased levels of NLRP3 and cleaved CASP1/Caspase1 in Becn1+/- microglia. Super-resolation microscopy revealed a very close association of NLRP3 aggregates and LC3-positive vesicles. Interestingly, CALCOCO2 colocalized with NLRP3 and its downregulation increased IL-1beta release. These data support the notion that selective autophagy can impact microglia activation by modulating IL-1beta and IL-18 production via NLRP3 degradation and thus present a mechanism how impaired autophagy could contribute to neuroinflammation in Alzheimer's disease., (© 2019 The Authors.)- Published
- 2019
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