Beclin1-driven Autophagy Modulates the Inflammatory Response of Microglia Via NLRP3

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2019 Jan 9

PMID 30617086

Citations 93

Authors

Judith Houtman

Kiara Freitag

Niclas Gimber

Jan Schmoranzer

Frank L Heppner

Marina Jendrach

Affiliations

Soon will be listed here.

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 mice exhibited increased expression of IL-1beta and IL-18 compared to wild-type microglia. 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 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.

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