Beclin1‐driven autophagy modulates the inflammatory response of microglia via NLRP 3

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. 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.

URB597 protects against NLRP3 inflammasome activation by inhibiting autophagy dysfunction in a rat model of chronic cerebral hypoperfusion

“…Interestingly, in our present study, p62 was seldom colocalized with NLRP3 after URB treatment, suggesting that p62 may be unnecessary for removing NLRP3 in the process of autophagy after URB treatment. We noticed that p62 is reported to be dispensable for removing damaged mitochondria, challenging the role of p62 in mitophagy [44][45][46]. Hence, we speculate p62-independent mitophagy might be one of the critical mechanisms involved in NLRP3 inflammasome clearance after URB treatment.…”

Autophagy in the Immunosuppressive Perivascular Microenvironment of Glioblastoma

“…Microglia, the tissue-resident macrophage population of the brain, also require autophagy to maintain their ability to phagocytose apoptotic cells, protein aggregates and debris, and its failure enhances inflammation as it occurs in macrophages [17]. Several publications show activation of primary mouse microglia or microglial cell lines after knockdown of autophagy genes (i.e., Atg5 or Atg7) [123][124][125], and characterize how the inflammatory response can be modulated by Beclin1-driven autophagy through NLRP3 degradation [126] (Figure 2).…”

Pharmacological Inhibition of HDAC6 Attenuates NLRP3 Inflammatory Response and Protects Dopaminergic Neurons in Experimental Models of Parkinson’s Disease

“…Once activated, NLRP3 would oligomerize to form inflammasome and promote maturation of caspase-1 and several proinflammatory cytokines including IL-1β and IL-18 (Shen et al, 2018). Although NLRP3 inflammasome signaling has generally been considered an immune cell-related inflammatory process (Zhou et al, 2016;Lee et al, 2018;Voet et al, 2018;Houtman et al, 2019), expression and activation of inflammasome components have also been reported in neurons (Ye et al, 2017;Teng et al, 2018;Cowie et al, 2019;Pronin et al, 2019); notably, Zhang et al (2016) demonstrated that neuronal activation of NLRP3 is involved in the pathogenesis of PD. However, the potential mechanisms regulating NLRP3 activity in PD are poorly understood.…”