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Beclin1‐driven autophagy modulates the inflammatory response of microglia via NLRP 3
Author(s) -
Houtman Judith,
Freitag Kiara,
Gimber Niclas,
Schmoranzer Jan,
Heppner Frank L,
Jendrach Marina
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201899430
Subject(s) - biology , microglia , autophagy , inflammatory response , inflammation , microbiology and biotechnology , immunology , genetics , apoptosis
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 BECN 1/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. Becn1 +/− APPPS 1 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 NLRP 3 and cleaved CASP 1/Caspase1 in Becn1 +/− microglia. Super‐resolation microscopy revealed a very close association of NLRP 3 aggregates and LC 3‐positive vesicles. Interestingly, CALCOCO 2 colocalized with NLRP 3 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 NLRP 3 degradation and thus present a mechanism how impaired autophagy could contribute to neuroinflammation in Alzheimer's disease.