Beclin1‐driven autophagy modulates the inflammatory response of microglia via NLRP3.

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. Becn1+/−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. Synopsis: Decreased autophagy in microglia, the resident immune cells of the CNS, modulates production of the proinflammatory cytokines IL‐1 beta and IL‐18 by selective degradation of NLRP3. Primary microglia from Becn1+/− mice release a higher amount of IL‐1 beta and IL‐18 compared to wild‐type microglia upon a proinflammatory stimulus.Microglia from Becn1+/− mice display an increase in crucial components of the NLRP3 inflammasome.Super‐resolution microscopy (SIM) reveals the presence of NLRP3 aggregates in autophagosomes indicating their degradation.The putative autophagic linker protein murine CALCOCO2 but not the established autophagic adaptor p62/SQSTM1 colocalizes with NLRP3 and its downregulation increases IL‐1 beta release from stimulated microglia. Inflammasome degradation to curb production of IL‐1beta and IL‐18 cytokines indicates a brain immune cell role for autophagy, whose loss in Alzheimer's disease may contribute to neuropathology. [ABSTRACT FROM AUTHOR]